Vitamin d receptor modulators

ABSTRACT

The present invention relates to novel, non-secosteroidal, diaryl compounds with vitamin D receptor (VDR) modulating activity that are less hypercalcemic than 1a,25 dihydroxy vitamin D3. These compounds are useful for treating bone disease and psoriasis.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims the benefit of priority under Title 35United States Code, section 119(e), of Provisional Patent ApplicationNo. 60/429,041 filed Nov. 22, 2002; the disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

Vitamin D₃ Receptor (VDR) is a ligand dependent transcription factorthat belongs to the superfamily of nuclear hormone receptors. The VDRprotein is 427 amino acids, with a molecular weight of ˜50 kDa. The VDRligand, 1α,25-dihydroxyvitamin D3 (the hormonally active form of VitaminD) has its action mediated by its interaction with the nuclear receptorknown as Vitamin D receptor (“VDR”). The VDR ligand,1α,25-dihydroxyvitamin D3 (1α,25(OH)₂D₃) acts upon a wide variety oftissues and cells both related to and unrelated to calcium and phosphatehomeostasis.

The activity 1α,25-dihydroxyvitamin D3 in various systems suggests wideclinical applications. However, use of conventional VDR ligands ishampered by their associated toxicity, namely hypercalcemia (elevatedserum calcium). Currently, 1α,25(OH)₂D₃, marketed as Rocaltrol®pharmaceutical agent (product of Hoffmann-La Roche), is administered tokidney failure patients undergoing chronic kidney dialysis to treathypocalcemia and the resultant metabolic bone disease. Other therapeuticagents, such as Calcipotriol® (synthetic analog of 1α,25(OH)₂D₃) showincreased separation of binding affinity on VDR from hypercalcemicactivity.

Chemical modifications of 1α,25(OH)₂D₃ have yielded analogs withattenuated calcium mobilization effects (R. Bouillon et. al., EndocrineRev. 1995, 16, 200-257). One such analog, Dovonex® pharmaceutical agent(product of Bristol-Meyers Squibb Co.), is currently used in Europe andthe United States as a topical treatment for mild to moderate psoriasis(K. Kragballe et. al., Br. J. Dermatol. 1988, 119, 223-230).

Other Vitamin D₃ mimics have been described in the publication, VitaminD Analogs: Mechanism of Action of Therapeutic Applications, by Nagpal,S.; Lu, J.; Boelm, M. F., Curr. Med. Chem. 2001, 8, 1661-1679.

Although some degree of separation between the beneficial action andcalcium raising (calcemic) effects has been achieved with these VDRligands, to date the separation has been insufficient to allow for oraladministration to treat conditions such as osteoporosis, cancers,leukemias, and severe psoriasis.

One example of a major class of disorder that could benefit from VDRmediated biological efficacy in the absence of hypercalcemia isosteoporosis. Osteoporosis is a systemic disorder characterized bydecreased bone mass and microarchitectural deterioration of bone tissueleading to bone fragility and increased susceptibility to fractures ofthe hip, spine, and wrist (World Health Organization WHO 1994).Osteoporosis affects an estimated 75 million people in the UnitedStates, Europe, and Japan.

Within the past few years, several antiresorptive therapies have beenintroduced. These include bisphosphonates, hormone replacement therapy(HRT), a selective estrogen receptor modulator (SERM), and calcitonins.These treatments reduce bone resorption, bone formation, and increasebone density. However, none of these treatments increase true bonevolume nor can they restore lost bone architecture.

Another major disorder that could benefits from VDR mediated biologicalactivity is psoriasis. Psoriasis is one of the most common dermatologicdiseases and is a chronic inflammatory skin condition characterized byerythematous, sharply demarcated papules and rounded plaques, covered bysilvery micaceous scale.

Synthetic VDR ligands with reduced calcemic potential have beensynthesized. For example, a class of bis-phenyl compounds stated tomimic 1α, 25-dihydroxyvitamin D₃ is described in U.S. Pat. No. 6,218,430and the article; “Novel nonsecosteroidal vitamin D mimics exertVDR-modulating activities with less calcium mobilization than 1α,25-Dihydroxyvitamin D₃”, by Marcus F. Boehm, et. al., Chemistry &Biology 1999, Vol 6, No. 5, pgs. 265-275.

Synthetic VDR ligands having an aryl-thiophene nucleus are described inU.S. provisional patent application Ser. No. 60/384,151, filed 29 May2002.

There remains a need for improved treatments using alternative orimproved pharmaceutical agents that mimic 1α, 25-dihydroxyvitamin D₃ tostimulate bone formation, restore bone quality, and treat other diseaseswithout the attendant disadvantage of hypercalcemia.

SUMMARY OF THE INVENTION

Novel compounds having a nucleus of formula “(A)” have been foundeffective as Vitamin D Receptor (VDR) modulators:

The compounds of the invention with VDR modulating activities arerepresented by formula (I)

wherein the variables R, R′, R₁, R₂, Z_(B), and Z_(C) are as hereinafterdefined. It is a discovery of this invention that compounds describedherein display the desirable cell differentiation and antiproliferativeeffects of 1,25(OH)₂D₃ with reduced calcium mobilization (calcemic)effects if substituent Z_(C) possesses a carbon atom linked group thatis directly connected (i.e., with no intervening non-carbon atom) to thearyl nucleus.

In another aspect, the present invention is directed towardspharmaceutical compositions containing pharmaceutically effectiveamounts of compounds of formulae (I) or a pharmaceutically acceptablesalt or prodrug thereof, either singly or in combination, together withpharmaceutically acceptable carriers and/or auxiliary agents.

Another aspect of the invention is a pharmaceutical formulation fortreatment or prevention of osteoporosis containing pharmaceuticallyeffective amounts of the vitamin D receptor modulator compound offormula (I) alone or together with pharmaceutically effective amounts ofco-agents conventionally used for the treatment of osteoporosis.

Another aspect of the invention is a pharmaceutical formulation fortreatment or prevention of psoriasis containing pharmaceuticallyeffective amounts of the vitamin D receptor modulator compound offormula (I) alone or together with pharmaceutically effective amounts ofco-agents conventionally used for the treatment of psoriasis.

Another aspect of the invention is a pharmaceutical formulation fortreatment or prevention of prostate cancer containing pharmaceuticallyeffective amounts of the vitamin D receptor modulator compound offormula (I) alone or together with pharmaceutically effective amounts ofco-agents conventionally used for the treatment of prostate cancer.

Another aspect of the invention is to use the compounds of the inventionto treat disease states responsive to Vitamin D receptor ligands.

Another aspect of the invention is the prevention and treatment of acne,actinic keratosis, alopecia, Alzheimer's disease, autoimmune induceddiabetes, bone fracture healing, breast cancer, Crohn's disease, coloncancer, Type I diabetes, host-graft rejection, hypercalcemia, Type IIdiabetes, leukemia, multiple sclerosis, insufficient sebum secretion,osteomalacia, insufficient dermal firmness, insufficient dermalhydration, myelodysplastic syndrome, psoriatic arthritis, renalosteodystrophy, rheumatoid arthritis, scleroderma, seborrheicdermatitis, skin cancer, systemic lupus erythematosis, ulcerativecolitis and wrinkles; by administering to a mammal in need thereof apharmaceutically effective amount of a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term, “abscess” refers to adverse complications often associatedwith surgery, trauma, or diseases that predispose the host to abscessformation from encapsulated bacteria lymphocytes, macrophages, and etc.

The term, “adhesion” refers to the adverse and abnormal union ofsurfaces normally separate by the formation of new fibrous tissueresulting from an inflammatory process.

The term, “Mustard” is inclusive of both sulfur mustards and nitrogenmustards, either alone or in any combination. Exemplary of suchcompounds are the vesicants; bis(2-chloroethyl) sulfide (Chemical AgentSymbol HD), Cl(CH₂)₂S(CH₂)₂Cl 1,2-bis(2-chloroethylthio)ethane (ChemicalAgent Symbol Q), Cl(CH₂)₂S(CH₂)₂S(CH₂)₂Cl;bis(2-chloroethylthioethyl)ether, Cl(CH₂)₂S(CH₂)O(CH₂)₂S(CH₂)₂Cl(Chemical Agent Symbol T); tris(2-chloroethyl) amine (Chemical AgentSymbol HN3)N(CH₂CH₂Cl)₃; N-methyl-2,2′-dichlorodiethylamine (ChemicalAgent Symbol NH2); and 2,2′-dichlorotriethylamine, CH₃CH₂N(CH₂CH₂Cl)₂(Chemical Agent Symbol NH1).

The term “branched C₃-C₅ alkyl” is an alkyl group selected from1-methylethyl; 1-methylpropyl; 2-methylpropyl; 1,1-dimethylethyl;1,1-dimethylpropyl; 1,2-dimethylpropyl; or 2,2-dimethylpropyl. Preferredbranched C₃-C₅ alkyl groups are 2-methylpropyl and 1,1-dimethylethyl,with the 1,1-dimethylethyl group being most preferred.

The term, “branched alkyl terminal group” is used to identify thesubstituent Z_(B) of Formula I of the Invention. The definingcharacteristic of the branched alkyl terminal group is that it is placedon the diphenyl nucleus other than on the phenyl ring bearing thesubstituent Z_(C) as shown, for example, in the structural formula (B);

The term, “carbon atom linked group” is used to identify the chemicalsubstituent Z_(C) in the Formula I definition of compounds of theinvention. Its defining characteristic is a carbon atom as the firstatom and point of attachment to the aryl ring to which it is attached.For example in the structural formula (C):

the arrow identifies the carbon atom linked directly to the aryl nucleusof formula (I). All compounds of the invention contain a carbon atomlinked group as the Z_(C) substituent.

The term “alkenyl” refers to aliphatic groups wherein the point ofattachment is a carbon-carbon double bond, for example vinyl,1-propenyl, and 1-cyclohexenyl. Alkenyl groups may be straight-chain,branched-chain, cyclic, or combinations thereof, and may be optionallysubstituted. Suitable alkenyl groups have from 2 to about 20 carbonatoms.

The term “C₁-C₅ alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain, and cyclic groups and any combinationsthereof. Alkyl groups may further be divided into “primary”,“secondary”, and “tertiary” alkyl groups. In primary alkyl groups, thecarbon atom of attachment is substituted with zero (methyl) or oneorganic radical. In secondary alkyl groups, the carbon atom ofattachment is substituted with two organic radicals. In tertiary alkylgroups, the carbon atom of attachment is substituted with three organicradicals. Examples of C₁-C₅ alkyl groups are methyl, ethyl, n-propyl,1-methylethyl; n-butyl, 1-methylpropyl; 2-methylpropyl;1,1-dimethylethyl; n-amyl, 1,1-dimethylpropyl; 1,2-dimethylpropyl; and2,2-dimethylpropyl.

The term, “bond” when used to describe a divalent linking groupindicates the absence of a divalent atom, for example in the group

when L₁ is —O—, L₂ is a bond, L₃ is —CH₂—, and R_(B) is tBu thestructural formula is

The term “cycloalkyl” includes organic radicals such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term, “cycloalkenyl” includes organic radicals such ascyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term, “C₁-C₅ fluoroalkyl” is an alkyl group containing fluorine andincludes organic radicals such as —CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃,—CH₂CF₃, —CH₂CHF₂, and —CH₂CH₂F, with —CF₃ being preferred.

The abbreviation, “Me” means methyl.

The abbreviation, “Et” means ethyl.

The abbreviation, “iPr” means 1-methylethyl.

The abbreviation, “tBu” means 1,1-dimethylethyl.

The abbreviation, “3Me3OH44DiMe-Pentyl” means3-methyl-3-hydroxy-4,4-dimethylpentyl.

The abbreviation, “3Me3OH44DiMe-Pentenyl” means3-methyl-3-hydroxy-4,4-dimethylpentenyl.

The abbreviation, “3Me3OH44DiMe-Pentynyl” means3-methyl-3-hydroxy-4,4-dimethylpentyl.

The abbreviation, “3Et3OH44DiMe-Pentyl” means3-ethyl-3-hydroxy-4,4-dimethylpentyl.

The abbreviation, “3Et3OH44DiMe-Pentenyl” means3-ethyl-3-hydroxy-4,4-dimethylpentenyl.

The abbreviation, “3Et3OH44DiMe-Pentynyl” means3-ethyl-3-hydroxy-4,4-dimethylpentynyl.

The term, “—CH₂—C(O)—N-pyrrolidine” refers to the radical represented bythe structural formula:

The term, “—CH₂—N-pyrrolidin-2-one” refers to the radical represented bythe structural formula:

The term, “—CH₂-(1-methylpyrrolidin-2-one-3-yl)” refers to the organicradical represented by the structural formula:

The term, “1,3,4-oxadiazolin-2-one-5-yl” refers to the organic radicalrepresented by the structural formula:

The term, “1,3,4-oxadiazolin-2-thione-5-yl” refers to the organicradical represented by the structural formula:

The terml, “imidazolidine-2,4-dione-5-yl” refers to the organic radicalrepresented by the structural formula:

The term, “isoxazol-3-ol-5-yl” refers to the organic radical representedby the structural formula:

The term, “3-methyl-3-hydroxy-4,4-dimethylpentyl” refers to the radicalhaving the structural formula:

The term, “3-methyl-3-hydroxy-4,4-dimethylpentenyl.” refers to theradical having the structural formula (both cis and trans isomers):

The term, “3-methyl-3-hydroxy-4,4-dimethylpentyl” refers to the radicalhaving the structural formula:

The term, “3-ethyl-3-hydroxy-4,4-dimethylpentynyl” refers to the radicalhaving the structural formula:

The term, “3-ethyl-3-hydroxy-4,4-dimethylpentenyl” refers to the radicalhaving the structural formula (both cis and trans isomers):

The term, “3-ethyl-3-hydroxy-4,4-dimethylpentynyl” refers to the radicalhaving the structural formula:

The term, “−5-ethylidene-1,3-thiazolidine-2,4-dione, refers to theradical represented by the structural formula:

The dotted line symbol crossing a solid line representing a bond

means that the bond so marked is the bond of attachment.

The structural formula representing the compounds of the invention withor without open display of all pendant hydrogen atoms are equivalent,for example:

is the same compound as

The term, “mammal” includes humans.

The term “ester” refers to compounds of the general formula; RO—C(O)R′,prepared for example, where a hydroxy group of an acid is replaced withan alkoxide group. For example, a carboxylic ester is one in which thehydroxy group of a carboxylic acid is replaced with an alkoxide. Estersmay derive from any acid comprising one or more hydroxy groups: forexample, carbonic acid, carbamic acids, phosphonic acids, and sulfonicacids.

The term “halo” refer to fluorine, chlorine, bromine, and iodine.

The term, “C₁-C₅ fluoroalkyl” is an alkyl group containing fluorine andincludes organic radicals such as —CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃,—CH₂CF₃, —CH₂CHF₂, and —CH₂CH₂F, with —CF₃ being preferred.

The term, “(Acidic Group)” means a carbon atom linked organic group thatacts as a proton donor capable of hydrogen bonding. Illustrative of an(Acidic Group) is a group selected from the following:

Compounds of the Invention:

The compounds of the invention with vitamin receptor modulating (VDRM)activities are represented by formula (I) or a pharmaceuticallyacceptable salt or a prodrug derivative thereof:

wherein;

R and R′ are independently C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, or together Rand R′ form a substituted or unsubstituted, saturated or unsaturatedcarbocyclic ring having from 3 to 8 carbon atoms;

R₁ and R₂ are independently selected from the group consisting ofhydrogen, halo, C₁-C₅ alkyl, C₁-C₅ fluoroalkyl, —O—C₁-C₅ alkyl, —S—C₁-C₅alkyl, —O—C₁-C₅ fluoroalkyl, —CN, —NO₂, acetyl, —S—C₁-C₅ fluoroalkyl,C₂-C₅ alkenyl, C₃-C₅ cycloalkyl, and C₃-C₅ cycloalkenyl;

Z_(B) is a group represented by the formula:

wherein

(L₁), -(L₂)-, and -(L₃)- is each a divalent linking groups independentlyselected from the group consisting of

a bond,

where m is 0, 1, or 2, and each R40 is independently hydrogen, C₁-C₅alkyl, or C₁-C₅ fluoroalkyl;

R_(B) is a branched C₃-C₅ alkyl;

Z_(C) is a carbon atom linked group selected from

-   -   —CO₂H,    -   CO₂Me,    -   CO₂Et,    -   C(O)CH₂S(O)Me,    -   C(O)CH₂S(O)Et,    -   C(O)CH₂S(O)₂Me,    -   C(O)CH₂S(O)₂Et,    -   C(O)CH₂CH₂S(O)Me,    -   C(O)CH₂CH₂S(O)Et,    -   C(O)CH₂CH₂S(O)₂Me,    -   C(O)CH₂CH₂S(O)₂Et,    -   C(O)CH(Me)CH₂CO₂H,    -   C(O)CH(Me)CH₂CO₂Me,    -   C(O)CH(Me)CH₂CO₂Et,    -   C(O)CH(Me)CH₂CO₂iPr,    -   C(O)CH(Me)CH₂CO₂tBu,    -   C(O)CH(Me)CH(Me)CO₂H,    -   C(O)CH(Me)CH(Me)CO₂Me,    -   C(O)CH(Me)CH(Me)CO₂Et,    -   C(O)CH(Me)CH(Me)CO₂iPr,    -   C(O)CH(Me)CH(Me)CO₂tBu,    -   C(O)CH(Me)C(Me)₂CO₂H,    -   C(O)CH(Me)C(Me)₂CO₂Me,    -   C(O)CH(Me)C(Me)₂CO₂Et,    -   C(O)CH(Me)C(Me)₂CO₂iPr,    -   C(O)CH(Me)C(Me)₂CO₂tBu,    -   C(O)CH(Me)CH(Et)CO₂H,    -   C(O)CH(Me)CH(Et)CO₂Me,    -   C(O)CH(Me)CH(Et)CO₂Et,    -   C(O)CH(Me)CH(Et)CO₂iPr,    -   C(O)CH(Me)CH(Et)CO₂tBu,    -   C(O)C(O)OH,    -   C(O)C(O)NH₂,    -   C(O)C(O)NHMe,    -   C(O)C(O)NMe₂,    -   C(O)NH₂,    -   C(O)NMe₂,    -   C(O)NH—CH₂—C(O)OH,    -   C(O)NH—CH₂—C(O)OMe,    -   C(O)NH—CH₂—C(O)OEt,    -   C(O)NH—CH₂—C(O)OiPr,    -   C(O)NH—CH₂—C(O)OtBu,    -   C(O)NH—CH(Me)-C(O)OH,    -   C(O)NH—CH(Me)-C(O)OMe,    -   C(O)NH—CH(Me)-C(O)OEt,    -   C(O)NH—CH(Me)-C(O)iPr,    -   C(O)NH—CH(Me)-C(O)tBu,    -   C(O)NH—CH(Et)-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OMe,    -   C(O)NH—C(Me)₂-C(O)OEt,    -   C(O)NH—C(Me)₂-C(O)iPr,    -   C(O)NH—C(Me)₂-C(O)tBu,    -   C(O)NH-CMe(Et)-C(O)OH,    -   C(O)NH—CH(F)—C(O)OH,    -   C(O)NH—CH(CF₃)—C(O)OH,    -   C(O)NH—CH(OH)—C(O)OH,    -   C(O)NH—CH(cyclopropyl)-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OH,    -   C(O)NH—CF(Me)-C(O)OH,    -   C(O)NH—C(Me)(CF₃)—C(O)OH,    -   C(O)NH—C(Me)(OH)—C(O)OH,    -   C(O)NH—C(Me)(cyclopropyl)CO₂H    -   C(O)NMe-CH₂—C(O)OH,    -   C(O)NMe-CH₂—C(O)OMe,    -   C(O)NMe-CH₂—C(O)OEt,    -   C(O)NMe-CH₂—C(O)OiPr,    -   C(O)NMe-CH₂—C(O)tBu,    -   C(O)NMe-CH₂—C(O)OH,    -   C(O)NMe-CH(Me)-C(O)OH,    -   C(O)NMe-CH(F)—C(O)OH,    -   C(O)NMe-CH(CF₃)—C(O)OH,    -   C(O)NMe-CH(OH)—C(O)OH,    -   C(O)NMe-CH(cyclopropyl)-C(O)OH,    -   C(O)NMe-C(Me)₂-C(O)OH,    -   C(O)NMe-CF(Me)-C(O)OH,    -   C(O)NMe-C(Me)(CF₃)—C(O)OH,    -   C(O)NMe-C(Me)(OH)—C(O)OH,    -   C(O)NMe-C(Me)(cyclopropyl)-C(O)OH,    -   C(O)NHS(O)Me,    -   C(O)NHSO₂Me,    -   C(O)—NH-5-tetrazolyl,    -   C(O)NHS(O)Me,    -   C(O)NHS(O)Et,    -   C(O)NHSO₂Me,    -   C(O)NHSO₂Et,    -   C(O)NHS(O)iPr,    -   C(O)NHSO₂iPr,    -   C(O)NHS(O)tBu,    -   C(O)NHSO₂tBu,    -   C(O)NHCH₂S(O)Me,    -   C(O)NHCH₂S(O)Et,    -   C(O)NHCH₂SO₂Me,    -   C(O)NHCH₂SO₂Et,    -   C(O)NHCH₂CH₂S(O)Me,    -   C(O)NHCH₂CH₂S(O)Et,    -   C(O)NHCH₂CH₂SO₂Me,    -   C(O)NHCH₂CH₂SO₂Et,    -   C(O)N(Me)S(O)Me,    -   C(O)N(Me)SO₂Me,    -   C(O)—N(Me)-5-tetrazolyl,    -   C(O)N(Me)S(O)Me,    -   C(O)N(Me)S(O)Et,    -   C(O)N(Me)SO₂Me,    -   C(O)N(Me)SO₂Et,    -   C(O)N(Me)S(O)iPr,    -   C(O)N(Me))SO₂iPr,    -   C(O)N(Me))S(O)tBu,    -   C(O)N(Me)SO₂tBu,    -   C(O)N(Me)CH₂S(O)Me,    -   C(O)N(Me)CH₂S(O)Et,    -   C(O)N(Me)CH₂SO₂Me,    -   C(O)N(Me)CH₂SO₂Et,    -   C(O)N(Me)CH₂CH₂S(O)Me,    -   C(O)N(Me)CH₂CH₂S(O)Et,    -   C(O)N(Me)CH₂CH₂SO₂Me,    -   C(O)N(Me)CH₂CH₂SO₂Et,    -   CH₂CO₂H,    -   CH₂-5-tetrazolyl,    -   CH₂CO₂Me,    -   CH₂CO₂Et,    -   CH₂NHS(O)Me,    -   CH₂NHS(O)Et,    -   CH₂NHSO₂Me,    -   CH₂NHSO₂Et,    -   CH₂NHS(O)iPr,    -   CH₂NHSO₂iPr,    -   CH₂NHS(O)tBu,    -   CH₂NHSO₂tBu,    -   CH₂NHCH₂CH₂SO₂CH₃,    -   CH₂NH(CH₂CO₂H),    -   CH₂N(C(O)Me)(CH₂CO₂H),    -   CH₂—N-pyrrolidin-2-one,    -   CH₂-(1-methylpyrrolidin-2-one-3-yl),    -   CH₂S(O)Me,    -   CH₂S(O)Et,    -   CH₂S(O)₂Me,    -   CH₂S(O)₂Et,    -   CH₂S(O)iPr,    -   CH₂S(O)₂iPr,    -   CH₂S(O)tBu,    -   CH₂S(O)₂tBu,    -   CH₂CO₂H, CH₂C(O)NH₂,    -   CH₂C(O)NMe₂,    -   CH₂C(O)NHMe,    -   CH₂C(O)—N-pyrrolidine,    -   CH₂S(O)₂Me, CH₂S(O)Me,    -   CH(OH)CO₂H,    -   CH(OH)C(O)NH₂,    -   CH(OH)C(O)NHMe,    -   CH(OH)C(O)NMe₂,    -   CH(OH)C(O)NEt₂,    -   CH₂CH₂CO₂H,    -   CH₂CH₂CO₂Me,    -   CH₂CH₂CO₂Et,    -   CH₂CH₂C(O)NH₂,    -   CH₂CH₂C(O)NHMe,    -   CH₂CH₂C(O)NMe₂,    -   CH₂CH₂-5-tetrazolyl,    -   CH₂CH₂S(O)₂Me,    -   CH₂CH₂S(O)Me,    -   CH₂CH₂S(O)₂Et,    -   CH₂CH₂S(O) Et,    -   CH₂CH₂S(O)iPr,    -   CH₂CH₂S(O)₂iPr,    -   CH₂CH₂S(O)tBu,    -   CH₂CH₂S(O)₂tBu,    -   CH₂CH₂S(O)NH₂,    -   CH₂CH₂S(O)NHMe,    -   CH₂CH₂S(O)NMe₂,    -   CH₂CH₂S(O)₂NH₂,    -   CH₂CH₂S(O)₂NHMe    -   CH₂CH₂S(O)₂NMe₂,    -   CH₂CH₂CH₂S(O)Me,    -   CH₂CH₂CH₂S(O)Et,    -   CH₂CH₂CH₂S(O)₂Me,    -   CH₂CH₂CH₂S(O)₂Et,        -   C(O)OH,        -   5-tetrazolyl,    -   C(O)—N(Me)-5-tetrazolyl,

-   -   1,3,4-oxadiazolin-2-one-5-yl,    -   imidazolidine-2,4-dione-5-yl,    -   isoxazol-3-ol-yl, or    -   1,3,4-oxadiazolin-2-thione-5-yl.

In the preceding formula (I) the divalent linking groups -(L1)- and-(L2)- and -(L3)- are understood (in the case of those having more thanone substituent) to be oriented in either direction, for example, wheredivalent linker (L1) has the identity —(CH₂)_(m)—O—, it may beconfigured:

Preferred compounds of the invention with VDR modulating activities arerepresented by formula (I) or a pharmaceutically acceptable salt or aprodrug derivative thereof:

wherein;

R and R′ are independently methyl, ethyl, propyl, or 1-methylethyl;

R₁ and R₂ are independently selected from the group consisting ofhydrogen, fluoro, —Cl, —CF₃, —CH₂F, —CHF₂, methoxy, ethoxy, vinyl,methyl, ethyl, propyl, 1-methylethyl, 1,1-dimethylethyl, butyl,1-methylpropyl, 2-methylpropyl, or cyclopropyl;

Z_(B) is a branched alkyl terminated group represented by the formula:

R_(B) is 1-methylethyl; 1-methylpropyl; 2-methylpropyl;1,1-dimethylethyl; 1,1-dimethylpropyl; 1,2-dimethylpropyl;2,2-dimethylpropyl; 3-methyl-3-hydroxy-4,4-dimethylpentyl;3-methyl-3-hydroxy-4,4-dimethylpentenyl;3-methyl-3-hydroxy-4,4-dimethylpentyl;3-ethyl-3-hydroxy-4,4-dimethylpentynyl;3-ethyl-3-hydroxy-4,4-dimethylpentenyl; or3-ethyl-3-hydroxy-4,4-dimethylpentynyl;

(L₁) and (L₂) and (L₃) are independently divalent linking groups where

L₁ is —O—, —CH₂—, —CHOH—, —CH(Me)—, —C(O)—, or —C(Me)OH—;

L₂ is —CH₂—, —CHOH—, —CH(Me)—, —C(O)—, or —C(Me)OH—; or

L₁ and L₂ taken together is the group

—CH₂—CH₂—,

—CH≡CH—, or

—C≡C—;

L₃ is a bond, —CH₂—, —CHOH—, —CH(Me)- -C(O)—, or —C(Me)OH—;

Z_(C) is a group selected from

-   -   C(O)CH₂S(O)Me,    -   C(O)CH₂S(O)Et,    -   C(O)CH₂S(O)₂Me,    -   C(O)CH₂S(O)₂Et,    -   C(O)CH₂CH₂S(O)Me,    -   C(O)CH₂CH₂S(O)Et,    -   C(O)CH₂CH₂S(O)₂Me,    -   C(O)CH₂CH₂S(O)₂Et,    -   C(O)CH(Me)CH₂CO₂H,    -   C(O)CH(Me)CH₂CO₂Me,    -   C(O)CH(Me)CH₂CO₂Et,    -   C(O)CH(Me)CH₂CO₂iPr,    -   C(O)CH(Me)CH₂CO₂tBu,    -   C(O)CH(Me)CH(Me)CO₂H,    -   C(O)CH(Me)CH(Me)CO₂Me,    -   C(O)CH(Me)CH(Me)CO₂Et,    -   C(O)CH(Me)CH(Me)CO₂iPr,    -   C(O)CH(Me)CH(Me)CO₂tBu,    -   C(O)CH(Me)C(Me)₂CO₂H,    -   C(O)CH(Me)C(Me)₂CO₂Me,    -   C(O)CH(Me)C(Me)₂CO₂Et,    -   C(O)CH(Me)C(Me)₂CO₂iPr,    -   C(O)CH(Me)C(Me)₂CO₂tBu,    -   C(O)CH(Me)CH(Et)CO₂H,    -   C(O)CH(Me)CH(Et)CO₂Me,    -   C(O)CH(Me)CH(Et)CO₂Et,    -   C(O)CH(Me)CH(Et)CO₂iPr,    -   C(O)CH(Me)CH(Et)CO₂tBu,    -   C(O)C(O)OH,    -   C(O)C(O)NH₂,    -   C(O)C(O)NHMe,    -   C(O)C(O)NMe₂,    -   C(O)NH₂,    -   C(O)NMe₂,    -   C(O)NH—CH₂—C(O)OH,    -   C(O)NH—CH₂—C(O)OMe,    -   C(O)NH—CH₂—C(O)OEt,    -   C(O)NH—CH₂—C(O)OiPr,    -   C(O)NH—CH₂—C(O)OtBu,    -   C(O)NH—CH(Me)-C(O)OH,    -   C(O)NH—CH(Me)-C(O)OMe,    -   C(O)NH—CH(Me)-C(O)OEt,    -   C(O)NH—CH(Me)-C(O)iPr,    -   C(O)NH—CH(Me)-C(O)tBu,    -   C(O)NH—CH(Et)-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OMe,    -   C(O)NH—C(Me)₂-C(O)OEt,    -   C(O)NH—C(Me)₂-C(O)iPr,    -   C(O)NH—C(Me)₂-C(O)tBu,    -   C(O)NH-CMe(Et)-C(O)OH,    -   C(O)NH—CH(F)—C(O)OH,    -   C(O)NH—CH(CF₃)—C(O)OH,    -   C(O)NH—CH(OH)—C(O)OH,    -   C(O)NH—CH(cyclopropyl)-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OH,    -   C(O)NH—CF(Me)-C(O)OH,    -   C(O)NH—C(Me)(CF₃)—C(O)OH,    -   C(O)NH—C(Me)(OH)—C(O)OH,    -   C(O)NH—C(Me)(cyclopropyl)CO₂H,    -   C(O)NMe-CH₂—C(O)OH,    -   C(O)NMe-CH₂—C(O)OMe,    -   C(O)NMe-CH₂—C(O)OEt,    -   C(O)NMe-CH₂—C(O)OiPr,    -   C(O)NMe-CH₂—C(O)tBu,    -   C(O)NMe-CH(Me)-C(O)OH,    -   C(O)NMe-CH(F)—C(O)OH,    -   C(O)NMe-CH(CF₃)—C(O)OH,    -   C(O)NMe-CH(OH)—C(O)OH,    -   C(O)NMe-CH(cyclopropyl)-C(O)OH,    -   C(O)NMe-C(Me)₂-C(O)OH,    -   C(O)NMe-CF(Me)-C(O)OH,    -   C(O)NMe-C(Me)(CF₃)—C(O)OH,    -   C(O)NMe-C(Me)(OH)—C(O)OH,    -   C(O)NMe-C(Me)(cyclopropyl)-C(O)OH, or    -   C(O)—N(Me)-5-tetrazolyl.

Other preferred compounds of the invention are those represented byformula (I) or a pharmaceutically acceptable salt or a prodrugderivative thereof:

wherein;

R and R′ are independently methyl or ethyl;

R₁ and R₂ are independently selected from the group consisting ofhydrogen, fluoro, —Cl, —CF₃, —CH₂F, —CHF₂, methoxy, ethoxy, vinyl,methyl, or cyclopropyl;

Z_(B) is a branched alkyl terminated selected from the formulae:

Z_(C) is selected from

-   -   C(O)NH₂,    -   C(O)NMe₂,    -   C(O)NH—CH₂—C(O)OH,    -   C(O)NH—CH₂—C(O)OMe,    -   C(O)NH—CH₂—C(O)OEt,    -   C(O)NH—CH₂—C(O)OiPr,    -   C(O)NH—CH₂—C(O)OtBu,    -   C(O)NH—CH(Me)-C(O)OH,    -   C(O)NH—CH(Me)-C(O)OMe,    -   C(O)NH—CH(Me)-C(O) OEt,    -   C(O)NH—CH(Me)-C(O)iPr,    -   C(O)NH—CH(Me)-C(O)tBu,    -   C(O)NH—CH(Et)-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OMe,    -   C(O)NH—C(Me)₂-C(O)OEt,    -   C(O)NH—C(Me)₂-C(O)iPr,    -   C(O)NH—C(Me)₂-C(O)tBu,    -   C(O)NH-CMe(Et)-C(O)OH,    -   C(O)NH—CH(F)—C(O)OH,    -   C(O)NH—CH(CF₃)—C(O)OH,    -   C(O)NH—CH(OH)—C(O)OH,    -   C(O)NH—CH(cyclopropyl)-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OH,    -   C(O)NH—C(Me)₂-C(O)OH,    -   C(O)NH—CF(Me)-C(O)OH,    -   C(O)NH—C(Me)(CF₃)—C(O)OH,    -   C(O)NH—C(Me)(OH)—C(O)OH,    -   C(O)NH—C(Me)(cyclopropyl)CO₂H,    -   C(O)NMe-CH₂—C(O)OH,    -   C(O)NMe-CH₂—C(O)OMe,    -   C(O)NMe-CH₂—C(O)OEt,    -   C(O)NMe-CH₂—C(O)OiPr,    -   C(O)NMe-CH₂—C(O)tBu,    -   C(O)NMe-CH(Me)-C(O)OH,    -   C(O)NMe-CH(F)—C(O)OH,    -   C(O)NMe-CH(CF₃)—C(O)OH,    -   C(O)NMe-CH(OH)—C(O)OH,    -   C(O)NMe-CH(cyclopropyl)-C(O)OH,    -   C(O)NMe-C(Me)₂-C(O)OH,    -   C(O)NMe-CF(Me)-C(O)OH,    -   C(O)NMe-C(Me)(CF₃)—C(O)OH,    -   C(O)NMe-C(Me)(OH)—C(O)OH,    -   C(O)NMe-C(Me)(cyclopropyl)-C(O)OH,    -   C(O)—N(Me)-5-tetrazolyl,

Particularly preferred is a compound or a pharmaceutically acceptablesalt or ester prodrug derivative thereof represented by structuralformulae (AA) to (DB) as follows:

Other particularly preferred compounds of the invention are those shownby the structural formulae C-1 to C-54 set out below. Pharmaceuticallyacceptable salts for prodrug derivatives of these compounds are alsopreferred.

Most preferred are the individual enantiomers or a mixture ofenantiomers represented by the formulae:

Additional particularly preferred are compounds or a pharmaceuticallyacceptable salt or prodrug derivative thereof selected from (TBU-1) to(TBU-86), as follows:

A compound or a pharmaceutically acceptable salt oran ester prodrugderivative thereof selected from (TBU-1) to (TBU-86), as follows:

Particularly preferred as a compound of the invention is the compound ora pharmaceutically acceptable salt or ester prodrug derivative of thecompound represented by the formula:

Particularly preferred as a compound of the invention is the compound ora pharmaceutically acceptable salt or ester prodrug derivative of thecompound represented by the formula:

For all of the above compounds of the invention defined by Formula (I)the preferred prodrug derivative is a methyl ester, ethyl esterN,N-diethylglycolamido ester or morpholinylethyl ester. In addition, forall of the above compounds of the invention the preferred salt is sodiumor potassium.

Other specific compounds that are preferred embodiments of thisinvention and are preferred for practicing the method of treatment ofthe invention are set out in the following Tables. All numbers in theTables cells reciting chemical species are to be understood assubscripts in chemical formulae, for example, in the first row of Table1, Compound No. 1, the symbol, “CO2Me” is to be understood as theconventional chemical nomenclature, —CO₂H—. Each row of the Tables 1 and2 represents a single compound having an identifying defining thespecific substituents in the structural formula displayed above eachTables, as follows:

Among other preferred compounds of the invention are those representedby the formula:

and pharmaceutically acceptable salts thereof; wherein;said compound is selected from a compound code numbered 1 thru 468, witheach compound having the specific selection of substituents R_(B),R_(C), L₁, L₂, and L₃ shown in the row following the compound codenumber, as set out in the following Table 1:

TABLE 1 No. R_(B) L₃ L₂ L₁ R_(C) 1 tBu C(O) CH2 O C(O)CH(Me)CH2CO2H 2tBu CHOH CH2 O C(O)CH(Me)CH2CO2H 3 tBu C(Me)OH CH2 O C(O)CH(Me)CH2CO2H 4tBu C(O) CH(Me) O C(O)CH(Me)CH2CO2H 5 tBu CHOH CH(Me) OC(O)CH(Me)CH2CO2H 6 tBu C(Me)OH CH(Me) O C(O)CH(Me)CH2CO2H 7 tBu C(O)CH2 O CO2H 8 tBu CHOH CH2 O CO2H 9 tBu C(Me)OH CH2 O CO2H 10 tBu C(O)CH(Me) O CO2H 11 tBu CHOH CH(Me) O CO2H 12 tBu C(Me)OH CH(Me) O CO2H 13tBu C(O) CH2 O C(O)NH2 14 tBu CHOH CH2 O C(O)NH2 15 tBu C(Me)OH CH2 OC(O)NH2 16 tBu C(O) CH(Me) O C(O)NH2 17 tBu CHOH CH(Me) O C(O)NH2 18 tBuC(Me)OH CH(Me) O C(O)NH2 19 tBu C(O) CH2 O C(O)NMe2 20 tBu CHOH CH2 OC(O)NMe2 21 tBu C(Me)OH CH2 O C(O)NMe2 22 tBu C(O) CH(Me) O C(O)NMe2 23tBu CHOH CH(Me) O C(O)NMe2 24 tBu C(Me)OH CH(Me) O C(O)NMe2 25 tBu C(O)CH2 O 5-tetrazolyl 26 tBu CHOH CH2 O 5-tetrazolyl 27 tBu C(Me)OH CH2 O5-tetrazolyl 28 tBu C(O) CH(Me) O 5-tetrazolyl 29 tBu CHOH CH(Me) O5-tetrazolyl 30 tBu C(Me)OH CH(Me) O 5-tetrazolyl 31 tBu C(O) CH2 OC(O)—NH-5-tetrazolyl 32 tBu CHOH CH2 O C(O)—NH-5-tetrazolyl 33 tBuC(Me)OH CH2 O C(O)—NH-5-tetrazolyl 34 tBu C(O) CH(Me) OC(O)—NH-5-tetrazolyl 35 tBu CHOH CH(Me) O C(O)—NH-5-tetrazolyl 36 tBuC(Me)OH CH(Me) O C(O)—NH-5-tetrazolyl 37 tBu C(O) CH2 O C(O)NHCH2SO2Me38 tBu CHOH CH2 O C(O)NHCH2SO2Me 39 tBu C(Me)OH CH2 O C(O)NHCH2SO2Me 40tBu C(O) CH(Me) O C(O)NHCH2SO2Me 41 tBu CHOH CH(Me) O C(O)NHCH2SO2Me 42tBu C(Me)OH CH(Me) O C(O)NHCH2SO2Me 43 tBu C(O) CH2 O C(O)NHCH2S(O)Me 44tBu CHOH CH2 O C(O)NHCH2S(O)Me 45 tBu C(Me)OH CH2 O C(O)NHCH2S(O)Me 46tBu C(O) CH(Me) O C(O)NHCH2S(O)Me 47 tBu CHOH CH(Me) O C(O)NHCH2S(O)Me48 tBu C(Me)OH CH(Me) O C(O)NHCH2S(O)Me 49 tBu C(O) CH2 OC(O)NHCH2CH2SO2Me 50 tBu CHOH CH2 O C(O)NHCH2CH2SO2Me 51 tBu C(Me)OH CH2O C(O)NHCH2CH2SO2Me 52 tBu C(O) CH(Me) O C(O)NHCH2CH2SO2Me 53 tBu CHOHCH(Me) O C(O)NHCH2CH2SO2Me 54 tBu C(Me)OH CH(Me) O C(O)NHCH2CH2SO2Me 55tBu C(O) CH2 O C(O)NHCH2CH2S(O)Me 56 tBu CHOH CH2 O C(O)NHCH2CH2S(O)Me57 tBu C(Me)OH CH2 O C(O)NHCH2CH2S(O)Me 58 tBu C(O) CH(Me) OC(O)NHCH2CH2S(O)Me 59 tBu CHOH CH(Me) O C(O)NHCH2CH2S(O)Me 60 tBuC(Me)OH CH(Me) O C(O)NHCH2CH2S(O)Me 61 tBu C(O) CH2 O C(O)NHSO2Me 62 tBuCHOH CH2 O C(O)NHSO2Me 63 tBu C(Me)OH CH2 O C(O)NHSO2Me 64 tBu C(O)CH(Me) O C(O)NHSO2Me 65 tBu CHOH CH(Me) O C(O)NHSO2Me 66 tBu C(Me)OHCH(Me) O C(O)NHSO2Me 67 tBu C(O) CH2 O C(O)NHS(O)Me 68 tBu CHOH CH2 OC(O)NHS(O)Me 69 tBu C(Me)OH CH2 O C(O)NHS(O)Me 70 tBu C(O) CH(Me) OC(O)NHS(O)Me 71 tBu CHOH CH(Me) O C(O)NHS(O)Me 72 tBu C(Me)OH CH(Me) OC(O)NHS(O)Me 73 tBu C(O) CH2 O C(O)NHSO2Et 74 tBu CHOH CH2 O C(O)NHSO2Et75 tBu C(Me)OH CH2 O C(O)NHSO2Et 76 tBu C(O) CH(Me) O C(O)NHSO2Et 77 tBuCHOH CH(Me) O C(O)NHSO2Et 78 tBu C(Me)OH CH(Me) O C(O)NHSO2Et 79 tBuC(O) CH2 O C(O)NHS(O)Et 80 tBu CHOH CH2 O C(O)NHS(O)Et 81 tBu C(Me)OHCH2 O C(O)NHS(O)Et 82 tBu C(O) CH(Me) O C(O)NHS(O)Et 83 tBu CHOH CH(Me)O C(O)NHS(O)Et 84 tBu C(Me)OH CH(Me) O C(O)NHS(O)Et 85 tBu C(O) CH2 OC(O)NHSO2iPr 86 tBu CHOH CH2 O C(O)NHSO2iPr 87 tBu C(Me)OH CH2 OC(O)NHSO2iPr 88 tBu C(O) CH(Me) O C(O)NHSO2iPr 89 tBu CHOH CH(Me) OC(O)NHSO2iPr 90 tBu C(Me)OH CH(Me) O C(O)NHSO2iPr 91 tBu C(O) CH2 OC(O)NHS(O)iPr 92 tBu CHOH CH2 O C(O)NHS(O)iPr 93 tBu C(Me)OH CH2 OC(O)NHS(O)iPr 94 tBu C(O) CH(Me) O C(O)NHS(O)iPr 95 tBu CHOH CH(Me) OC(O)NHS(O)iPr 96 tBu C(Me)OH CH(Me) O C(O)NHS(O)iPr 97 tBu C(O) CH2 OC(O)NHSO2tBu 98 tBu CHOH CH2 O C(O)NHSO2tBu 99 tBu C(Me)OH CH2 OC(O)NHSO2tBu 100 tBu C(O) CH(Me) O C(O)NHSO2tBu 101 tBu CHOH CH(Me) OC(O)NHSO2tBu 102 tBu C(Me)OH CH(Me) O C(O)NHSO2tBu 103 tBu C(O) CH2 OC(O)NHS(O)tBu 104 tBu CHOH CH2 O C(O)NHS(O)tBu 105 tBu C(Me)OH CH2 OC(O)NHS(O)tBu 106 tBu C(O) CH(Me) O C(O)NHS(O)tBu 107 tBu CHOH CH(Me) OC(O)NHS(O)tBu 108 tBu C(Me)OH CH(Me) O C(O)NHS(O)tBu 109 tBu C(O) CH2 OCH2NHSO2Me 110 tBu CHOH CH2 O CH2NHSO2Me 111 tBu C(Me)OH CH2 OCH2NHSO2Me 112 tBu C(O) CH(Me) O CH2NHSO2Me 113 tBu CHOH CH(Me) OCH2NHSO2Me 114 tBu C(Me)OH CH(Me) O CH2NHSO2Me 115 tBu C(O) CH2 OCH2NHS(O)Me 116 tBu CHOH CH2 O CH2NHS(O)Me 117 tBu C(Me)OH CH2 OCH2NHS(O)Me 118 tBu C(O) CH(Me) O CH2NHS(O)Me 119 tBu CHOH CH(Me) OCH2NHS(O)Me 120 tBu C(Me)OH CH(Me) O CH2NHS(O)Me 121 tBu C(O) CH2 OCH2NHSO2Et 122 tBu CHOH CH2 O CH2NHSO2Et 123 tBu C(Me)OH CH2 OCH2NHSO2Et 124 tBu C(O) CH(Me) O CH2NHSO2Et 125 tBu CHOH CH(Me) OCH2NHSO2Et 126 tBu C(Me)OH CH(Me) O CH2NHSO2Et 127 tBu C(O) CH2 OCH2NHS(O)Et 128 tBu CHOH CH2 O CH2NHS(O)Et 129 tBu C(Me)OH CH2 OCH2NHS(O)Et 130 tBu C(O) CH(Me) O CH2NHS(O)Et 131 tBu CHOH CH(Me) OCH2NHS(O)Et 132 tBu C(Me)OH CH(Me) O CH2NHS(O)Et 133 tBu C(O) CH2 OCH2NHSO2iPr 134 tBu CHOH CH2 O CH2NHSO2iPr 135 tBu C(Me)OH CH2 OCH2NHSO2iPr 136 tBu C(O) CH(Me) O CH2NHSO2iPr 137 tBu CHOH CH(Me) OCH2NHSO2iPr 138 tBu C(Me)OH CH(Me) O CH2NHSO2iPr 139 tBu C(O) CH2 OCH2NHS(O)iPr 140 tBu CHOH CH2 O CH2NHS(O)iPr 141 tBu C(Me)OH CH2 OCH2NHS(O)iPr 142 tBu C(O) CH(Me) O CH2NHS(O)iPr 143 tBu CHOH CH(Me) OCH2NHS(O)iPr 144 tBu C(Me)OH CH(Me) O CH2NHS(O)iPr 145 tBu C(O) CH2 OCH2NHSO2tBu 146 tBu CHOH CH2 O CH2NHSO2tBu 147 tBu C(Me)OH CH2 OCH2NHSO2tBu 148 tBu C(O) CH(Me) O CH2NHSO2tBu 149 tBu CHOH CH(Me) OCH2NHSO2tBu 150 tBu C(Me)OH CH(Me) O CH2NHSO2tBu 151 tBu C(O) CH2 OCH2NHS(O)tBu 152 tBu CHOH CH2 O CH2NHS(O)tBu 153 tBu C(Me)OH CH2 OCH2NHS(O)tBu 154 tBu C(O) CH(Me) O CH2NHS(O)tBu 155 tBu CHOH CH(Me) OCH2NHS(O)tBu 156 tBu C(Me)OH CH(Me) O CH2NHS(O)tBu 157 tBu C(O) CH2 OCH2—N-pyrrolidin-2-one 158 tBu CHOH CH2 O CH2—N-pyrrolidin-2-one 159 tBuC(Me)OH CH2 O CH2—N-pyrrolidin-2-one 160 tBu C(O) CH(Me) OCH2—N-pyrrolidin-2-one 161 tBu CHOH CH(Me) O CH2—N-pyrrolidin-2-one 162tBu C(Me)OH CH(Me) O CH2—N-pyrrolidin-2-one 163 tBu C(O) CH2 OCH2-(1-methylpyrrolidin-2- one-3-yl) 164 tBu CHOH CH2 OCH2-(1-methylpyrrolidin-2- one-3-yl) 165 tBu C(Me)OH CH2 OCH2-(1-methylpyrrolidin-2- one-3-yl) 166 tBu C(O) CH(Me) OCH2-(1-methylpyrrolidin-2- one-3-yl) 167 tBu CHOH CH(Me) OCH2-(1-methylpyrrolidin-2- one-3-yl) 168 tBu C(Me)OH CH(Me) OCH2-(1-methylpyrrolidin-2- one-3-yl) 169 tBu C(O) CH2 O CH2CO2Me 170 tBuCHOH CH2 O CH2CO2Me 171 tBu C(Me)OH CH2 O CH2CO2Me 172 tBu C(O) CH(Me) OCH2CO2Me 173 tBu CHOH CH(Me) O CH2CO2Me 174 tBu C(Me)OH CH(Me) OCH2CO2Me 175 tBu C(O) CH2 O CH2CO2H 176 tBu CHOH CH2 O CH2CO2H 177 tBuC(Me)OH CH2 O CH2CO2H 178 tBu C(O) CH(Me) O CH2CO2H 179 tBu CHOH CH(Me)O CH2CO2H 180 tBu C(Me)OH CH(Me) O CH2CO2H 181 tBu C(O) CH2 O CH2C(O)NH2182 tBu CHOH CH2 O CH2C(O)NH2 183 tBu C(Me)OH CH2 O CH2C(O)NH2 184 tBuC(O) CH(Me) O CH2C(O)NH2 185 tBu CHOH CH(Me) O CH2C(O)NH2 186 tBuC(Me)OH CH(Me) O CH2C(O)NH2 187 tBu C(O) CH2 O CH2C(O)NMe2 188 tBu CHOHCH2 O CH2C(O)NMe2 189 tBu C(Me)OH CH2 O CH2C(O)NMe2 190 tBu C(O) CH(Me)O CH2C(O)NMe2 191 tBu CHOH CH(Me) O CH2C(O)NMe2 192 tBu C(Me)OH CH(Me) OCH2C(O)NMe2 193 tBu C(O) CH2 O CH2C(O)—N-pyrrolidine 194 tBu CHOH CH2 OCH2C(O)—N-pyrrolidine 195 tBu C(Me)OH CH2 O CH2C(O)—N-pyrrolidine 196tBu C(O) CH(Me) O CH2C(O)—N-pyrrolidine 197 tBu CHOH CH(Me) OCH2C(O)—N-pyrrolidine 198 tBu C(Me)OH CH(Me) O CH2C(O)—N-pyrrolidine 199tBu C(O) CH2 O CH2-5-tetrazolyl 200 tBu CHOH CH2 O CH2-5-tetrazolyl 201tBu C(Me)OH CH2 O CH2-5-tetrazolyl 202 tBu C(O) CH(Me) OCH2-5-tetrazolyl 203 tBu CHOH CH(Me) O CH2-5-tetrazolyl 204 tBu C(Me)OHCH(Me) O CH2-5-tetrazolyl 205 tBu C(O) CH2 O C(O)C(O)OH 206 tBu CHOH CH2O C(O)C(O)OH 207 tBu C(Me)OH CH2 O C(O)C(O)OH 208 tBu C(O) CH(Me) OC(O)C(O)OH 209 tBu CHOH CH(Me) O C(O)C(O)OH 210 tBu C(Me)OH CH(Me) OC(O)C(O)OH 211 tBu C(O) CH2 O CH(OH)C(O)OH 212 tBu CHOH CH2 OCH(OH)C(O)OH 213 tBu C(Me)OH CH2 O CH(OH)C(O)OH 214 tBu C(O) CH(Me) OCH(OH)C(O)OH 215 tBu CHOH CH(Me) O CH(OH)C(O)OH 216 tBu C(Me)OH CH(Me) OCH(OH)C(O)OH 217 tBu C(O) CH2 O C(O)C(O)NH2 218 tBu CHOH CH2 OC(O)C(O)NH2 219 tBu C(Me)OH CH2 O C(O)C(O)NH2 220 tBu C(O) CH(Me) OC(O)C(O)NH2 221 tBu CHOH CH(Me) O C(O)C(O)NH2 222 tBu C(Me)OH CH(Me) OC(O)C(O)NH2 223 tBu C(O) CH2 O CH(OH)C(O)NH2 224 tBu CHOH CH2 OCH(OH)C(O)NH2 225 tBu C(Me)OH CH2 O CH(OH)C(O)NH2 226 tBu C(O) CH(Me) OCH(OH)C(O)NH2 227 tBu CHOH CH(Me) O CH(OH)C(O)NH2 228 tBu C(Me)OH CH(Me)O CH(OH)C(O)NH2 229 tBu C(O) CH2 O C(O)C(O)NMe2 230 tBu CHOH CH2 OC(O)C(O)NMe2 231 tBu C(Me)OH CH2 O C(O)C(O)NMe2 232 tBu C(O) CH(Me) OC(O)C(O)NMe2 233 tBu CHOH CH(Me) O C(O)C(O)NMe2 234 tBu C(Me)OH CH(Me) OC(O)C(O)NMe2 235 tBu C(O) CH2 O CH(OH)C(O)NMe2 236 tBu CHOH CH2 OCH(OH)C(O)NMe2 237 tBu C(Me)OH CH2 O CH(OH)C(O)NMe2 238 tBu C(O) CH(Me)O CH(OH)C(O)NMe2 239 tBu CHOH CH(Me) O CH(OH)C(O)NMe2 240 tBu C(Me)OHCH(Me) O CH(OH)C(O)NMe2 241 tBu C(O) CH2 O CH2CH2CO2H 242 tBu CHOH CH2 OCH2CH2CO2H 243 tBu C(Me)OH CH2 O CH2CH2CO2H 244 tBu C(O) CH(Me) OCH2CH2CO2H 245 tBu CHOH CH(Me) O CH2CH2CO2H 246 tBu C(Me)OH CH(Me) OCH2CH2CO2H 247 tBu C(O) CH2 O CH2CH2C(O)NH2 248 tBu CHOH CH2 OCH2CH2C(O)NH2 249 tBu C(Me)OH CH2 O CH2CH2C(O)NH2 250 tBu C(O) CH(Me) OCH2CH2C(O)NH2 251 tBu CHOH CH(Me) O CH2CH2C(O)NH2 252 tBu C(Me)OH CH(Me)O CH2CH2C(O)NH2 253 tBu C(O) CH2 O CH2CH2C(O)NMe2 254 tBu CHOH CH2 OCH2CH2C(O)NMe2 255 tBu C(Me)OH CH2 O CH2CH2C(O)NMe2 256 tBu C(O) CH(Me)O CH2CH2C(O)NMe2 257 tBu CHOH CH(Me) O CH2CH2C(O)NMe2 258 tBu C(Me)OHCH(Me) O CH2CH2C(O)NMe2 259 tBu C(O) CH2 O CH2CH2-5-tetrazolyl 260 tBuCHOH CH2 O CH2CH2-5-tetrazolyl 261 tBu C(Me)OH CH2 O CH2CH2-5-tetrazolyl262 tBu C(O) CH(Me) O CH2CH2-5-tetrazolyl 263 tBu CHOH CH(Me) OCH2CH2-5-tetrazolyl 264 tBu C(Me)OH CH(Me) O CH2CH2-5-tetrazolyl 265 tBuC(O) CH2 O CH2S(O)2Me 266 tBu CHOH CH2 O CH2S(O)2Me 267 tBu C(Me)OH CH2O CH2S(O)2Me 268 tBu C(O) CH(Me) O CH2S(O)2Me 269 tBu CHOH CH(Me) OCH2S(O)2Me 270 tBu C(Me)OH CH(Me) O CH2S(O)2Me 271 tBu C(O) CH2 OCH2S(O)Me 272 tBu CHOH CH2 O CH2S(O2Me 273 tBu C(Me)OH CH2 O CH2S(O)Me274 tBu C(O) CH(Me) O CH2S(O)Me 275 tBu CHOH CH(Me) O CH2S(O)Me 276 tBuC(Me)OH CH(Me) O CH2S(O)Me 277 tBu C(O) CH2 O CH2CH2S(O)2Me 278 tBu CHOHCH2 O CH2CH2S(O)2Me 279 tBu C(Me)OH CH2 O CH2CH2S(O)2Me 280 tBu C(O)CH(Me) O CH2CH2S(O)2Me 281 tBu CHOH CH(Me) O CH2CH2S(O)2Me 282 tBuC(Me)OH CH(Me) O CH2CH2S(O)2Me 283 tBu C(O) CH2 O CH2CH2S(O)Me 284 tBuCHOH CH2 O CH2CH2S(O)Me 285 tBu C(Me)OH CH2 O CH2CH2S(O)Me 286 tBu C(O)CH(Me) O CH2CH2S(O)Me 287 tBu CHOH CH(Me) O CH2CH2S(O)Me 288 tBu C(Me)OHCH(Me) O CH2CH2S(O)Me 289 tBu C(O) CH2 O CH2CH2CH2S(O)2Me 290 tBu CHOHCH2 O CH2CH2CH2S(O)2Me 291 tBu C(Me)OH CH2 O CH2CH2CH2S(O)2Me 292 tBuC(O) CH(Me) O CH2CH2CH2S(O)2Me 293 tBu CHOH CH(Me) O CH2CH2CH2S(O)2Me294 tBu C(Me)OH CH(Me) O CH2CH2CH2S(O)2Me 295 tBu C(O) CH2 OCH2CH2CH2S(O)Me 296 tBu CHOH CH2 O CH2CH2CH2S(O)Me 297 tBu C(Me)OH CH2 OCH2CH2CH2S(O)Me 298 tBu C(O) CH(Me) O CH2CH2CH2S(O)Me 299 tBu CHOHCH(Me) O CH2CH2CH2S(O)Me 300 tBu C(Me)OH CH(Me) O CH2CH2CH2S(O)Me 301tBu C(O) CH2 O CH2S(O)2Et 302 tBu CHOH CH2 O CH2S(O)2Et 303 tBu C(Me)OHCH2 O CH2S(O)2Et 304 tBu C(O) CH(Me) O CH2S(O)2Et 305 tBu CHOH CH(Me) OCH2S(O)2Et 306 tBu C(Me)OH CH(Me) O CH2S(O)2Et 307 tBu C(O) CH2 OCH2S(O)Et 308 tBu CHOH CH2 O CH2S(O)Et 309 tBu C(Me)OH CH2 O CH2S(O)Et310 tBu C(O) CH(Me) O CH2S(O)Et 311 tBu CHOH CH(Me) O CH2S(O)Et 312 tBuC(Me)OH CH(Me) O CH2S(O)Et 313 tBu C(O) CH2 O CH2CH2S(O)2Et 314 tBu CHOHCH2 O CH2CH2S(O)2Et 315 tBu C(Me)OH CH2 O CH2CH2S(O)2Et 316 tBu C(O)CH(Me) O CH2CH2S(O)2Et 317 tBu CHOH CH(Me) O CH2CH2S(O)2Et 318 tBuC(Me)OH CH(Me) O CH2CH2S(O)2Et 319 tBu C(O) CH2 O CH2CH2S(O)Et 320 tBuCHOH CH2 O CH2CH2S(O)Et 321 tBu C(Me)OH CH2 O CH2CH2S(O)Et 322 tBu C(O)CH(Me) O CH2CH2S(O)Et 323 tBu CHOH CH(Me) O CH2CH2S(O)Et 324 tBu C(Me)OHCH(Me) O CH2CH2S(O)Et 325 tBu C(O) CH2 O CH2CH2CH2S(O)2Et 326 tBu CHOHCH2 O CH2CH2CH2S(O)2Et 327 tBu C(Me)OH CH2 O CH2CH2CH2S(O)2Et 328 tBuC(O) CH(Me) O CH2CH2CH2S(O)2Et 329 tBu CHOH CH(Me) O CH2CH2CH2S(O)2Et330 tBu C(Me)OH CH(Me) O CH2CH2CH2S(O)2Et 331 tBu C(O) CH2 OCH2CH2CH2S(O)Et 332 tBu CHOH CH2 O CH2CH2CH2S(O)Et 333 tBu C(Me)OH CH2 OCH2CH2CH2S(O)Et 334 tBu C(O) CH(Me) O CH2CH2CH2S(O)Et 335 tBu CHOHCH(Me) O CH2CH2CH2S(O)Et 336 tBu C(Me)OH CH(Me) O CH2CH2CH2S(O)Et 337tBu C(O) CH2 O CH2S(O)2iPr 338 tBu CHOH CH2 O CH2S(O)2iPr 339 tBuC(Me)OH CH2 O CH2S(O)2iPr 340 tBu C(O) CH(Me) O CH2S(O)2iPr 341 tBu CHOHCH(Me) O CH2S(O)2iPr 342 tBu C(Me)OH CH(Me) O CH2S(O)2iPr 343 tBu C(O)CH2 O CH2S(O)iPr 344 tBu CHOH CH2 O CH2S(O)iPr 345 tBu C(Me)OH CH2 OCH2S(O)iPr 346 tBu C(O) CH(Me) O CH2S(O)iPr 347 tBu CHOH CH(Me) OCH2S(O)iPr 348 tBu C(Me)OH CH(Me) O CH2S(O)iPr 349 tBu C(O) CH2 OCH2CH2S(O)2iPr 350 tBu CHOH CH2 O CH2CH2S(O)2iPr 351 tBu C(Me)OH CH2 OCH2CH2S(O)2iPr 352 tBu C(O) CH(Me) O CH2CH2S(O)2iPr 353 tBu CHOH CH(Me)O CH2CH2S(O)2iPr 354 tBu C(Me)OH CH(Me) O CH2CH2S(O)2iPr 355 tBu C(O)CH2 O CH2CH2S(O)iPr 356 tBu CHOH CH2 O CH2CH2S(O)iPr 357 tBu C(Me)OH CH2O CH2CH2S(O)iPr 358 tBu C(O) CH(Me) O CH2CH2S(O)iPr 359 tBu CHOH CH(Me)O CH2CH2S(O)iPr 360 tBu C(Me)OH CH(Me) O CH2CH2S(O)iPr 361 tBu C(O) CH2O CH2S(O)2tBu 362 tBu CHOH CH2 O CH2S(O)2tBu 363 tBu C(Me)OH CH2 OCH2S(O)2tBu 364 tBu C(O) CH(Me) O CH2S(O)2tBu 365 tBu CHOH CH(Me) OCH2S(O)2tBu 366 tBu C(Me)OH CH(Me) O CH2S(O)2tBu 367 tBu C(O) CH2 OCH2S(O)tBu 368 tBu CHOH CH2 O CH2S(O)tBu 369 tBu C(Me)OH CH2 OCH2S(O)tBu 370 tBu C(O) CH(Me) O CH2S(O)tBu 371 tBu CHOH CH(Me) OCH2S(O)tBu 372 tBu C(Me)OH CH(Me) O CH2S(O)tBu 373 tBu C(O) CH2 OCH2CH2S(O)2tBu 374 tBu CHOH CH2 O CH2CH2S(O)2tBu 375 tBu C(Me)OH CH2 OCH2CH2S(O)2tBu 376 tBu C(O) CH(Me) O CH2CH2S(O)2tBu 377 tBu CHOH CH(Me)O CH2CH2S(O)2tBu 378 tBu C(Me)OH CH(Me) O CH2CH2S(O)2tBu 379 tBu C(O)CH2 O CH2CH2S(O)tBu 380 tBu CHOH CH2 O CH2CH2S(O)tBu 381 tBu C(Me)OH CH2O CH2CH2S(O)tBu 382 tBu C(O) CH(Me) O CH2CH2S(O)tBu 383 tBu CHOH CH(Me)O CH2CH2S(O)tBu 384 tBu C(Me)OH CH(Me) O CH2CH2S(O)tBu 385 tBu C(O) CH2O CH2CH2S(O)2NH2 386 tBu CHOH CH2 O CH2CH2S(O)2NH2 387 tBu C(Me)OH CH2 OCH2CH2S(O)2NH2 388 tBu C(O) CH(Me) O CH2CH2S(O)2NH2 389 tBu CHOH CH(Me)O CH2CH2S(O)2NH2 390 tBu C(Me)OH CH(Me) O CH2CH2S(O)2NH2 391 tBu C(O)CH2 O CH2CH2S(O)NH2 392 tBu CHOH CH2 O CH2CH2S(O)NH2 393 tBu C(Me)OH CH2O CH2CH2S(O)NH2 394 tBu C(O) CH(Me) O CH2CH2S(O)NH2 395 tBu CHOH CH(Me)O CH2CH2S(O)NH2 396 tBu C(Me)OH CH(Me) O CH2CH2S(O)NH2 397 tBu C(O) CH2O CH2CH2S(O)2NMe2 398 tBu CHOH CH2 O CH2CH2S(O)2NMe2 399 tBu C(Me)OH CH2O CH2CH2S(O)2NMe2 400 tBu C(O) CH(Me) O CH2CH2S(O)2NMe2 401 tBu CHOHCH(Me) O CH2CH2S(O)2NMe2 402 tBu C(Me)OH CH(Me) O CH2CH2S(O)2NMe2 403tBu C(O) CH2 O CH2CH2S(O)NMe2 404 tBu CHOH CH2 O CH2CH2S(O)NMe2 405 tBuC(Me)OH CH2 O CH2CH2S(O)NMe2 406 tBu C(O) CH(Me) O CH2CH2S(O)NMe2 407tBu CHOH CH(Me) O CH2CH2S(O)NMe2 408 tBu C(Me)OH CH(Me) O CH2CH2S(O)NMe2409 tBu C(O) CH2 O C(O)CH2S(O)2Me 410 tBu CHOH CH2 O C(O)CH2S(O)2Me 411tBu C(Me)OH CH2 O C(O)CH2S(O)2Me 412 tBu C(O) CH(Me) O C(O)CH2S(O)2Me413 tBu CHOH CH(Me) O C(O)CH2S(O)2Me 414 tBu C(Me)OH CH(Me) OC(O)CH2S(O)2Me 415 tBu C(O) CH2 O C(O)CH2S(O)Me 416 tBu CHOH CH2 OC(O)CH2S(O)Me 417 tBu C(Me)OH CH2 O C(O)CH2S(O)Me 418 tBu C(O) CH(Me) OC(O)CH2S(O)Me 419 tBu CHOH CH(Me) O C(O)CH2S(O)Me 420 tBu C(Me)OH CH(Me)O C(O)CH2S(O)Me 421 tBu C(O) CH2 O C(O)CH2CH2S(O)2Me 422 tBu CHOH CH2 OC(O)CH2CH2S(O)2Me 423 tBu C(Me)OH CH2 O C(O)CH2CH2S(O)2Me 424 tBu C(O)CH(Me) O C(O)CH2CH2S(O)2Me 425 tBu CHOH CH(Me) O C(O)CH2CH2S(O)2Me 426tBu C(Me)OH CH(Me) O C(O)CH2CH2S(O)2Me 427 tBu C(O) CH2 OC(O)CH2CH2S(O)Me 428 tBu CHOH CH2 O C(O)CH2CH2S(O)Me 429 tBu C(Me)OH CH2O C(O)CH2CH2S(O)Me 430 tBu C(O) CH(Me) O C(O)CH2CH2S(O)Me 431 tBu CHOHCH(Me) O C(O)CH2CH2S(O)Me 432 tBu C(Me)OH CH(Me) O C(O)CH2CH2S(O)Me 433tBu C(O) CH2 O CH2CH2CH2S(O)2NH2 434 tBu CHOH CH2 O CH2CH2CH2S(O)2NH2435 tBu C(Me)OH CH2 O CH2CH2CH2S(O)2NH2 436 tBu C(O) CH(Me) OCH2CH2CH2S(O)2NH2 437 tBu CHOH CH(Me) O CH2CH2CH2S(O)2NH2 438 tBuC(Me)OH CH(Me) O CH2CH2CH2S(O)2NH2 439 tBu C(O) CH2 O CH2CH2CH2S(O)NH2440 tBu CHOH CH2 O CH2CH2CH2S(O)NH2 441 tBu C(Me)OH CH2 OCH2CH2CH2S(O)NH2 442 tBu C(O) CH(Me) O CH2CH2CH2S(O)NH2 443 tBu CHOHCH(Me) O CH2CH2CH2S(O)NH2 444 tBu C(Me)OH CH(Me) O CH2CH2CH2S(O)NH2 445tBu C(O) CH2 CH2 1,3,4-oxadiazolin-2-one-5-yl 446 tBu CHOH CH2 CH21,3,4-oxadiazolin-2-one-5-yl 447 tBu C(Me)OH CH2 CH21,3,4-oxadiazolin-2-one-5-yl 448 tBu C(O) CH(Me) CH21,3,4-oxadiazolin-2-one-5-yl 449 tBu CHOH CH(Me) CH21,3,4-oxadiazolin-2-one-5-yl 450 tBu C(Me)OH CH(Me) CH21,3,4-oxadiazolin-2-one-5-yl 451 tBu C(O) CH2 CH21,3,4-oxadiazolin-2-thione- 5-yl 452 tBu CHOH CH2 CH21,3,4-oxadiazolin-2-thione- 5-yl 453 tBu C(Me)OH CH2 CH21,3,4-oxadiazolin-2-thione- 5-yl 454 tBu C(O) CH(Me) CH21,3,4-oxadiazolin-2-thione- 5-yl 455 tBu CHOH CH(Me) CH21,3,4-oxadiazolin-2-thione- 5-yl 456 tBu C(Me)OH CH(Me) CH21,3,4-oxadiazolin-2-thione- 5-yl 457 tBu C(O) CH2 CH2imidazolidine-2,4-dione-5-yl 458 tBu CHOH CH2 CH2imidazolidine-2,4-dione-5-yl 459 tBu C(Me)OH CH2 CH2imidazolidine-2,4-dione-5-yl 460 tBu C(O) CH(Me) CH2imidazolidine-2,4-dione-5-yl 461 tBu CHOH CH(Me) CH2imidazolidine-2,4-dione-5-yl 462 tBu C(Me)OH CH(Me) CH2imidazolidine-2,4-dione-5-yl 463 tBu C(O) CH2 CH2 isoxazol-3-ol-5-yl 464tBu CHOH CH2 CH2 isoxazol-3-ol-5-yl 465 tBu C(Me)OH CH2 CH2isoxazol-3-ol-5-yl 466 tBu C(O) CH(Me) CH2 isoxazol-3-ol-5-yl 467 tBuCHOH CH(Me) CH2 isoxazol-3-ol-5-yl 468 tBu C(Me)OH CH(Me) CH2isoxazol-3-ol-5-yl

Among other preferred compounds of the invention are also thoserepresented by the formula:

and pharmaceutically acceptable salts thereof; wherein;said compound is selected from a compound code numbered 1A thru 468A,with each compound having the specific selection of substituents R_(B),R_(C), L₁, L₂, and L₃ shown in the row following the compound codenumber, as set out in the following Table 2:

TABLE 2 R_(B) L₃ L₂ L₁ R_(C) 1A tBu C(O) CH2 CH2 C(O)CH(Me)CH2CO2H 2AtBu CHOH CH2 CH2 C(O)CH(Me)CH2CO2H 3A tBu C(Me)OH CH2 CH2C(O)CH(Me)CH2CO2H 4A tBu C(O) CH(Me) CH2 C(O)CH(Me)CH2CO2H 5A tBu CHOHCH(Me) CH2 C(O)CH(Me)CH2CO2H 6A tBu C(Me)OH CH(Me) CH2 C(O)CH(Me)CH2CO2H7A tBu C(O) CH2 CH2 CO2H 8A tBu CHOH CH2 CH2 CO2H 9A tBu C(Me)OH CH2 CH2CO2H 10A tBu C(O) CH(Me) CH2 CO2H 11A tBu CHOH CH(Me) CH2 CO2H 12A tBuC(Me)OH CH(Me) CH2 CO2H 13A tBu C(O) CH2 CH2 C(O)NH2 14A tBu CHOH CH2CH2 C(O)NH2 15A tBu C(Me)OH CH2 CH2 C(O)NH2 16A tBu C(O) CH(Me) CH2C(O)NH2 17A tBu CHOH CH(Me) CH2 C(O)NH2 18A tBu C(Me)OH CH(Me) CH2C(O)NH2 19A tBu C(O) CH2 CH2 C(O)NMe2 20A tBu CHOH CH2 CH2 C(O)NMe2 21AtBu C(Me)OH CH2 CH2 C(O)NMe2 22A tBu C(O) CH(Me) CH2 C(O)NMe2 23A tBuCHOH CH(Me) CH2 C(O)NMe2 24A tBu C(Me)OH CH(Me) CH2 C(O)NMe2 25A tBuC(O) CH2 CH2 5-tetrazolyl 26A tBu CHOH CH2 CH2 5-tetrazolyl 27A tBuC(Me)OH CH2 CH2 5-tetrazolyl 28A tBu C(O) CH(Me) CH2 5-tetrazolyl 29AtBu CHOH CH(Me) CH2 5-tetrazolyl 30A tBu C(Me)OH CH(Me) CH2 5-tetrazolyl31A tBu C(O) CH2 CH2 C(O)—NH-5-tetrazolyl 32A tBu CHOH CH2 CH2C(O)—NH-5-tetrazolyl 33A tBu C(Me)OH CH2 CH2 C(O)—NH-5-tetrazolyl 34AtBu C(O) CH(Me) CH2 C(O)—NH-5-tetrazolyl 35A tBu CHOH CH(Me) CH2C(O)—NH-5-tetrazolyl 36A tBu C(Me)OH CH(Me) CH2 C(O)—NH-5-tetrazolyl 37AtBu C(O) CH2 CH2 C(O)NHCH2SO2Me 38A tBu CHOH CH2 CH2 C(O)NHCH2SO2Me 39AtBu C(Me)OH CH2 CH2 C(O)NHCH2SO2Me 40A tBu C(O) CH(Me) CH2C(O)NHCH2SO2Me 41A tBu CHOH CH(Me) CH2 C(O)NHCH2SO2Me 42A tBu C(Me)OHCH(Me) CH2 C(O)NHCH2SO2Me 43A tBu C(O) CH2 CH2 C(O)NHCH2S(O)Me 44A tBuCHOH CH2 CH2 C(O)NHCH2S(O)Me 45A tBu C(Me)OH CH2 CH2 C(O)NHCH2S(O)Me 46AtBu C(O) CH(Me) CH2 C(O)NHCH2S(O)Me 47A tBu CHOH CH(Me) CH2C(O)NHCH2S(O)Me 48A tBu C(Me)OH CH(Me) CH2 C(O)NHCH2S(O)Me 49A tBu C(O)CH2 CH2 C(O)NHCH2CH2SO2Me 50A tBu CHOH CH2 CH2 C(O)NHCH2CH2SO2Me 51A tBuC(Me)OH CH2 CH2 C(O)NHCH2CH2SO2Me 52A tBu C(O) CH(Me) CH2C(O)NHCH2CH2SO2Me 53A tBu CHOH CH(Me) CH2 C(O)NHCH2CH2SO2Me 54A tBuC(Me)OH CH(Me) CH2 C(O)NHCH2CH2SO2Me 55A tBu C(O) CH2 CH2C(O)NHCH2CH2S(O)Me 56A tBu CHOH CH2 CH2 C(O)NHCH2CH2S(O)Me 57A tBuC(Me)OH CH2 CH2 C(O)NHCH2CH2S(O)Me 58A tBu C(O) CH(Me) CH2C(O)NHCH2CH2S(O)Me 59A tBu CHOH CH(Me) CH2 C(O)NHCH2CH2S(O)Me 60A tBuC(Me)OH CH(Me) CH2 C(O)NHCH2CH2S(O)Me 61A tBu C(O) CH2 CH2 C(O)NHSO2Me62A tBu CHOH CH2 CH2 C(O)NHSO2Me 63A tBu C(Me)OH CH2 CH2 C(O)NHSO2Me 64AtBu C(O) CH(Me) CH2 C(O)NHSO2Me 65A tBu CHOH CH(Me) CH2 C(O)NHSO2Me 66AtBu C(Me)OH CH(Me) CH2 C(O)NHSO2Me 67A tBu C(O) CH2 CH2 C(O)NHS(O)Me 68AtBu CHOH CH2 CH2 C(O)NHS(O)Me 69A tBu C(Me)OH CH2 CH2 C(O)NHS(O)Me 70AtBu C(O) CH(Me) CH2 C(O)NHS(O)Me 71A tBu CHOH CH(Me) CH2 C(O)NHS(O)Me72A tBu C(Me)OH CH(Me) CH2 C(O)NHS(O)Me 73A tBu C(O) CH2 CH2 C(O)NHSO2Et74A tBu CHOH CH2 CH2 C(O)NHSO2Et 75A tBu C(Me)OH CH2 CH2 C(O)NHSO2Et 76AtBu C(O) CH(Me) CH2 C(O)NHSO2Et 77A tBu CHOH CH(Me) CH2 C(O)NHSO2Et 78AtBu C(Me)OH CH(Me) CH2 C(O)NHSO2Et 79A tBu C(O) CH2 CH2 C(O)NHS(O)Et 80AtBu CHOH CH2 CH2 C(O)NHS(O)Et 81A tBu C(Me)OH CH2 CH2 C(O)NHS(O)Et 82AtBu C(O) CH(Me) CH2 C(O)NHS(O)Et 83A tBu CHOH CH(Me) CH2 C(O)NHS(O)Et84A tBu C(Me)OH CH(Me) CH2 C(O)NHS(O)Et 85A tBu C(O) CH2 CH2C(O)NHSO2iPr 86A tBu CHOH CH2 CH2 C(O)NHSO2iPr 87A tBu C(Me)OH CH2 CH2C(O)NHSO2iPr 88A tBu C(O) CH(Me) CH2 C(O)NHSO2iPr 89A tBu CHOH CH(Me)CH2 C(O)NHSO2iPr 90A tBu C(Me)OH CH(Me) CH2 C(O)NHSO2iPr 91A tBu C(O)CH2 CH2 C(O)NHS(O)iPr 92A tBu CHOH CH2 CH2 C(O)NHS(O)iPr 93A tBu C(Me)OHCH2 CH2 C(O)NHS(O)iPr 94A tBu C(O) CH(Me) CH2 C(O)NHS(O)iPr 95A tBu CHOHCH(Me) CH2 C(O)NHS(O)iPr 96A tBu C(Me)OH CH(Me) CH2 C(O)NHS(O)iPr 97AtBu C(O) CH2 CH2 C(O)NHSO2tBu 98A tBu CHOH CH2 CH2 C(O)NHSO2tBu 99A tBuC(Me)OH CH2 CH2 C(O)NHSO2tBu 100A tBu C(O) CH(Me) CH2 C(O)NHSO2tBu 101AtBu CHOH CH(Me) CH2 C(O)NHSO2tBu 102A tBu C(Me)OH CH(Me) CH2C(O)NHSO2tBu 103A tBu C(O) CH2 CH2 C(O)NHS(O)tBu 104A tBu CHOH CH2 CH2C(O)NHS(O)tBu 105A tBu C(Me)OH CH2 CH2 C(O)NHS(O)tBu 106A tBu C(O)CH(Me) CH2 C(O)NHS(O)tBu 107A tBu CHOH CH(Me) CH2 C(O)NHS(O)tBu 108A tBuC(Me)OH CH(Me) CH2 C(O)NHS(O)tBu 109A tBu C(O) CH2 CH2 CH2NHSO2Me 110AtBu CHOH CH2 CH2 CH2NHSO2Me 111A tBu C(Me)OH CH2 CH2 CH2NHSO2Me 112A tBuC(O) CH(Me) CH2 CH2NHSO2Me 113A tBu CHOH CH(Me) CH2 CH2NHSO2Me 114A tBuC(Me)OH CH(Me) CH2 CH2NHSO2Me 115A tBu C(O) CH2 CH2 CH2NHS(O)Me 116A tBuCHOH CH2 CH2 CH2NHS(O)Me 117A tBu C(Me)OH CH2 CH2 CH2NHS(O)Me 118A tBuC(O) CH(Me) CH2 CH2NHS(O)Me 119A tBu CHOH CH(Me) CH2 CH2NHS(O)Me 120AtBu C(Me)OH CH(Me) CH2 CH2NHS(O)Me 121A tBu C(O) CH2 CH2 CH2NHSO2Et 122AtBu CHOH CH2 CH2 CH2NHSO2Et 123A tBu C(Me)OH CH2 CH2 CH2NHSO2Et 124A tBuC(O) CH(Me) CH2 CH2NHSO2Et 125A tBu CHOH CH(Me) CH2 CH2NHSO2Et 126A tBuC(Me)OH CH(Me) CH2 CH2NHSO2Et 127A tBu C(O) CH2 CH2 CH2NHS(O)Et 128A tBuCHOH CH2 CH2 CH2NHS(O)Et 129A tBu C(Me)OH CH2 CH2 CH2NHS(O)Et 130A tBuC(O) CH(Me) CH2 CH2NHS(O)Et 131A tBu CHOH CH(Me) CH2 CH2NHS(O)Et 132AtBu C(Me)OH CH(Me) CH2 CH2NHS(O)Et 133A tBu C(O) CH2 CH2 CH2NHSO2iPr134A tBu CHOH CH2 CH2 CH2NHSO2iPr 135A tBu C(Me)OH CH2 CH2 CH2NHSO2iPr136A tBu C(O) CH(Me) CH2 CH2NHSO2iPr 137A tBu CHOH CH(Me) CH2CH2NHSO2iPr 138A tBu C(Me)OH CH(Me) CH2 CH2NHSO2iPr 139A tBu C(O) CH2CH2 CH2NHS(O)iPr 140A tBu CHOH CH2 CH2 CH2NHS(O)iPr 141A tBu C(Me)OH CH2CH2 CH2NHS(O)iPr 142A tBu C(O) CH(Me) CH2 CH2NHS(O)iPr 143A tBu CHOHCH(Me) CH2 CH2NHS(O)iPr 144A tBu C(Me)OH CH(Me) CH2 CH2NHS(O)iPr 145AtBu C(O) CH2 CH2 CH2NHSO2tBu 146A tBu CHOH CH2 CH2 CH2NHSO2tBu 147A tBuC(Me)OH CH2 CH2 CH2NHSO2tBu 148A tBu C(O) CH(Me) CH2 CH2NHSO2tBu 149AtBu CHOH CH(Me) CH2 CH2NHSO2tBu 150A tBu C(Me)OH CH(Me) CH2 CH2NHSO2tBu151A tBu C(O) CH2 CH2 CH2NHS(O)tBu 152A tBu CHOH CH2 CH2 CH2NHS(O)tBu153A tBu C(Me)OH CH2 CH2 CH2NHS(O)tBu 154A tBu C(O) CH(Me) CH2CH2NHS(O)tBu 155A tBu CHOH CH(Me) CH2 CH2NHS(O)tBu 156A tBu C(Me)OHCH(Me) CH2 CH2NHS(O)tBu 157A tBu C(O) CH2 CH2 CH2—N-pyrrolidin-2-one158A tBu CHOH CH2 CH2 CH2—N-pyrrolidin-2-one 159A tBu C(Me)OH CH2 CH2CH2—N-pyrrolidin-2-one 160A tBu C(O) CH(Me) CH2 CH2—N-pyrrolidin-2-one161A tBu CHOH CH(Me) CH2 CH2—N-pyrrolidin-2-one 162A tBu C(Me)OH CH(Me)CH2 CH2—N-pyrrolidin-2-one 163A tBu C(O) CH2 CH2CH2-(1-methylpyrrolidin-2- one-3-yl) 164A tBu CHOH CH2 CH2CH2-(1-methylpyrrolidin-2- one-3-yl) 165A tBu C(Me)OH CH2 CH2CH2-(1-methylpyrrolidin-2- one-3-yl) 166A tBu C(O) CH(Me) CH2CH2-(1-methylpyrrolidin-2- one-3-yl) 167A tBu CHOH CH(Me) CH2CH2-(1-methylpyrrolidin-2- one-3-yl) 168A tBu C(Me)OH CH(Me) CH2CH2-(1-methylpyrrolidin-2- one-3-yl) 169A tBu C(O) CH2 CH2 CH2CO2Me 170AtBu CHOH CH2 CH2 CH2CO2Me 171A tBu C(Me)OH CH2 CH2 CH2CO2Me 172A tBuC(O) CH(Me) CH2 CH2CO2Me 173A tBu CHOH CH(Me) CH2 CH2CO2Me 174A tBuC(Me)OH CH(Me) CH2 CH2CO2Me 175A tBu C(O) CH2 CH2 CH2CO2H 176A tBu CHOHCH2 CH2 CH2CO2H 177A tBu C(Me)OH CH2 CH2 CH2CO2H 178A tBu C(O) CH(Me)CH2 CH2CO2H 179A tBu CHOH CH(Me) CH2 CH2CO2H 180A tBu C(Me)OH CH(Me) CH2CH2CO2H 181A tBu C(O) CH2 CH2 CH2C(O)NH2 182A tBu CHOH CH2 CH2CH2C(O)NH2 183A tBu C(Me)OH CH2 CH2 CH2C(O)NH2 184A tBu C(O) CH(Me) CH2CH2C(O)NH2 185A tBu CHOH CH(Me) CH2 CH2C(O)NH2 186A tBu C(Me)OH CH(Me)CH2 CH2C(O)NH2 187A tBu C(O) CH2 CH2 CH2C(O)NMe2 188A tBu CHOH CH2 CH2CH2C(O)NMe2 189A tBu C(Me)OH CH2 CH2 CH2C(O)NMe2 190A tBu C(O) CH(Me)CH2 CH2C(O)NMe2 191A tBu CHOH CH(Me) CH2 CH2C(O)NMe2 192A tBu C(Me)OHCH(Me) CH2 CH2C(O)NMe2 193A tBu C(O) CH2 CH2 CH2C(O)—N-pyrrolidine 194AtBu CHOH CH2 CH2 CH2C(O)—N-pyrrolidine 195A tBu C(Me)OH CH2 CH2CH2C(O)—N-pyrrolidine 196A tBu C(O) CH(Me) CH2 CH2C(O)—N-pyrrolidine197A tBu CHOH CH(Me) CH2 CH2C(O)—N-pyrrolidine 198A tBu C(Me)OH CH(Me)CH2 CH2C(O)—N-pyrrolidine 199A tBu C(O) CH2 CH2 CH2-5-tetrazolyl 200AtBu CHOH CH2 CH2 CH2-5-tetrazolyl 201A tBu C(Me)OH CH2 CH2CH2-5-tetrazolyl 202A tBu C(O) CH(Me) CH2 CH2-5-tetrazolyl 203A tBu CHOHCH(Me) CH2 CH2-5-tetrazolyl 204A tBu C(Me)OH CH(Me) CH2 CH2-5-tetrazolyl205A tBu C(O) CH2 CH2 C(O)C(O)OH 206A tBu CHOH CH2 CH2 C(O)C(O)OH 207AtBu C(Me)OH CH2 CH2 C(O)C(O)OH 208A tBu C(O) CH(Me) CH2 C(O)C(O)OH 209AtBu CHOH CH(Me) CH2 C(O)C(O)OH 210A tBu C(Me)OH CH(Me) CH2 C(O)C(O)OH211A tBu C(O) CH2 CH2 CH(OH)C(O)OH 212A tBu CHOH CH2 CH2 CH(OH)C(O)OH213A tBu C(Me)OH CH2 CH2 CH(OH)C(O)OH 214A tBu C(O) CH(Me) CH2CH(OH)C(O)OH 215A tBu CHOH CH(Me) CH2 CH(OH)C(O)OH 216A tBu C(Me)OHCH(Me) CH2 CH(OH)C(O)OH 217A tBu C(O) CH2 CH2 C(O)C(O)NH2 218A tBu CHOHCH2 CH2 C(O)C(O)NH2 219A tBu C(Me)OH CH2 CH2 C(O)C(O)NH2 220A tBu C(O)CH(Me) CH2 C(O)C(O)NH2 221A tBu CHOH CH(Me) CH2 C(O)C(O)NH2 222A tBuC(Me)OH CH(Me) CH2 C(O)C(O)NH2 223A tBu C(O) CH2 CH2 CH(OH)C(O)NH2 224AtBu CHOH CH2 CH2 CH(OH)C(O)NH2 225A tBu C(Me)OH CH2 CH2 CH(OH)C(O)NH2226A tBu C(O) CH(Me) CH2 CH(OH)C(O)NH2 227A tBu CHOH CH(Me) CH2CH(OH)C(O)NH2 228A tBu C(Me)OH CH(Me) CH2 CH(OH)C(O)NH2 229A tBu C(O)CH2 CH2 C(O)C(O)NMe2 230A tBu CHOH CH2 CH2 C(O)C(O)NMe2 231A tBu C(Me)OHCH2 CH2 C(O)C(O)NMe2 232A tBu C(O) CH(Me) CH2 C(O)C(O)NMe2 233A tBu CHOHCH(Me) CH2 C(O)C(O)NMe2 234A tBu C(Me)OH CH(Me) CH2 C(O)C(O)NMe2 235AtBu C(O) CH2 CH2 CH(OH)C(O)NMe2 236A tBu CHOH CH2 CH2 CH(OH)C(O)NMe2237A tBu C(Me)OH CH2 CH2 CH(OH)C(O)NMe2 238A tBu C(O) CH(Me) CH2CH(OH)C(O)NMe2 239A tBu CHOH CH(Me) CH2 CH(OH)C(O)NMe2 240A tBu C(Me)OHCH(Me) CH2 CH(OH)C(O)NMe2 241A tBu C(O) CH2 CH2 CH2CH2CO2H 242A tBu CHOHCH2 CH2 CH2CH2CO2H 243A tBu C(Me)OH CH2 CH2 CH2CH2CO2H 244A tBu C(O)CH(Me) CH2 CH2CH2CO2H 245A tBu CHOH CH(Me) CH2 CH2CH2CO2H 246A tBuC(Me)OH CH(Me) CH2 CH2CH2CO2H 247A tBu C(O) CH2 CH2 CH2CH2C(O)NH2 248AtBu CHOH CH2 CH2 CH2CH2C(O)NH2 249A tBu C(Me)OH CH2 CH2 CH2CH2C(O)NH2250A tBu C(O) CH(Me) CH2 CH2CH2C(O)NH2 251A tBu CHOH CH(Me) CH2CH2CH2C(O)NH2 252A tBu C(Me)OH CH(Me) CH2 CH2CH2C(O)NH2 253A tBu C(O)CH2 CH2 CH2CH2C(O)NMe2 254A tBu CHOH CH2 CH2 CH2CH2C(O)NMe2 255A tBuC(Me)OH CH2 CH2 CH2CH2C(O)NMe2 256A tBu C(O) CH(Me) CH2 CH2CH2C(O)NMe2257A tBu CHOH CH(Me) CH2 CH2CH2C(O)NMe2 258A tBu C(Me)OH CH(Me) CH2CH2CH2C(O)NMe2 259A tBu C(O) CH2 CH2 CH2CH2-5-tetrazolyl 260A tBu CHOHCH2 CH2 CH2CH2-5-tetrazolyl 261A tBu C(Me)OH CH2 CH2 CH2CH2-5-tetrazolyl262A tBu C(O) CH(Me) CH2 CH2CH2-5-tetrazolyl 263A tBu CHOH CH(Me) CH2CH2CH2-5-tetrazolyl 264A tBu C(Me)OH CH(Me) CH2 CH2CH2-5-tetrazolyl 265AtBu C(O) CH2 CH2 CH2S(O)2Me 266A tBu CHOH CH2 CH2 CH2S(O)2Me 267A tBuC(Me)OH CH2 CH2 CH2S(O)2Me 268A tBu C(O) CH(Me) CH2 CH2S(O)2Me 269A tBuCHOH CH(Me) CH2 CH2S(O)2Me 270A tBu C(Me)OH CH(Me) CH2 CH2S(O)2Me 271AtBu C(O) CH2 CH2 CH2S(O)Me 272A tBu CHOH CH2 CH2 CH2S(O2Me 273A tBuC(Me)OH CH2 CH2 CH2S(O)Me 274A tBu C(O) CH(Me) CH2 CH2S(O)Me 275A tBuCHOH CH(Me) CH2 CH2S(O)Me 276A tBu C(Me)OH CH(Me) CH2 CH2S(O)Me 277A tBuC(O) CH2 CH2 CH2CH2S(O)2Me 278A tBu CHOH CH2 CH2 CH2CH2S(O)2Me 279A tBuC(Me)OH CH2 CH2 CH2CH2S(O)2Me 280A tBu C(O) CH(Me) CH2 CH2CH2S(O)2Me281A tBu CHOH CH(Me) CH2 CH2CH2S(O)2Me 282A tBu C(Me)OH CH(Me) CH2CH2CH2S(O)2Me 283A tBu C(O) CH2 CH2 CH2CH2S(O)Me 284A tBu CHOH CH2 CH2CH2CH2S(O)Me 285A tBu C(Me)OH CH2 CH2 CH2CH2S(O)Me 286A tBu C(O) CH(Me)CH2 CH2CH2S(O)Me 287A tBu CHOH CH(Me) CH2 CH2CH2S(O)Me 288A tBu C(Me)OHCH(Me) CH2 CH2CH2S(O)Me 289A tBu C(O) CH2 CH2 CH2CH2CH2S(O)2Me 290A tBuCHOH CH2 CH2 CH2CH2CH2S(O)2Me 291A tBu C(Me)OH CH2 CH2 CH2CH2CH2S(O)2Me292A tBu C(O) CH(Me) CH2 CH2CH2CH2S(O)2Me 293A tBu CHOH CH(Me) CH2CH2CH2CH2S(O)2Me 294A tBu C(Me)OH CH(Me) CH2 CH2CH2CH2S(O)2Me 295A tBuC(O) CH2 CH2 CH2CH2CH2S(O)Me 296A tBu CHOH CH2 CH2 CH2CH2CH2S(O)Me 297AtBu C(Me)OH CH2 CH2 CH2CH2CH2S(O)Me 298A tBu C(O) CH(Me) CH2CH2CH2CH2S(O)Me 299A tBu CHOH CH(Me) CH2 CH2CH2CH2S(O)Me 300A tBuC(Me)OH CH(Me) CH2 CH2CH2CH2S(O)Me 301A tBu C(O) CH2 CH2 CH2S(O)2Et 302AtBu CHOH CH2 CH2 CH2S(O)2Et 303A tBu C(Me)OH CH2 CH2 CH2S(O)2Et 304A tBuC(O) CH(Me) CH2 CH2S(O)2Et 305A tBu CHOH CH(Me) CH2 CH2S(O)2Et 306A tBuC(Me)OH CH(Me) CH2 CH2S(O)2Et 307A tBu C(O) CH2 CH2 CH2S(O)Et 308A tBuCHOH CH2 CH2 CH2S(O)Et 309A tBu C(Me)OH CH2 CH2 CH2S(O)Et 310A tBu C(O)CH(Me) CH2 CH2S(O)Et 311A tBu CHOH CH(Me) CH2 CH2S(O)Et 312A tBu C(Me)OHCH(Me) CH2 CH2S(O)Et 313A tBu C(O) CH2 CH2 CH2CH2S(O)2Et 314A tBu CHOHCH2 CH2 CH2CH2S(O)2Et 315A tBu C(Me)OH CH2 CH2 CH2CH2S(O)2Et 316A tBuC(O) CH(Me) CH2 CH2CH2S(O)2Et 317A tBu CHOH CH(Me) CH2 CH2CH2S(O)2Et318A tBu C(Me)OH CH(Me) CH2 CH2CH2S(O)2Et 319A tBu C(O) CH2 CH2CH2CH2S(O)Et 320A tBu CHOH CH2 CH2 CH2CH2S(O)Et 321A tBu C(Me)OH CH2 CH2CH2CH2S(O)Et 322A tBu C(O) CH(Me) CH2 CH2CH2S(O)Et 323A tBu CHOH CH(Me)CH2 CH2CH2S(O)Et 324A tBu C(Me)OH CH(Me) CH2 CH2CH2S(O)Et 325A tBu C(O)CH2 CH2 CH2CH2CH2S(O)2Et 326A tBu CHOH CH2 CH2 CH2CH2CH2S(O)2Et 327A tBuC(Me)OH CH2 CH2 CH2CH2CH2S(O)2Et 328A tBu C(O) CH(Me) CH2CH2CH2CH2S(O)2Et 329A tBu CHOH CH(Me) CH2 CH2CH2CH2S(O)2Et 330A tBuC(Me)OH CH(Me) CH2 CH2CH2CH2S(O)2Et 331A tBu C(O) CH2 CH2CH2CH2CH2S(O)Et 332A tBu CHOH CH2 CH2 CH2CH2CH2S(O)Et 333A tBu C(Me)OHCH2 CH2 CH2CH2CH2S(O)Et 334A tBu C(O) CH(Me) CH2 CH2CH2CH2S(O)Et 335AtBu CHOH CH(Me) CH2 CH2CH2CH2S(O)Et 336A tBu C(Me)OH CH(Me) CH2CH2CH2CH2S(O)Et 337A tBu C(O) CH2 CH2 CH2S(O)2iPr 338A tBu CHOH CH2 CH2CH2S(O)2iPr 339A tBu C(Me)OH CH2 CH2 CH2S(O)2iPr 340A tBu C(O) CH(Me)CH2 CH2S(O)2iPr 341A tBu CHOH CH(Me) CH2 CH2S(O)2iPr 342A tBu C(Me)OHCH(Me) CH2 CH2S(O)2iPr 343A tBu C(O) CH2 CH2 CH2S(O)iPr 344A tBu CHOHCH2 CH2 CH2S(O)iPr 345A tBu C(Me)OH CH2 CH2 CH2S(O)iPr 346A tBu C(O)CH(Me) CH2 CH2S(O)iPr 347A tBu CHOH CH(Me) CH2 CH2S(O)iPr 348A tBuC(Me)OH CH(Me) CH2 CH2S(O)iPr 349A tBu C(O) CH2 CH2 CH2CH2S(O)2iPr 350AtBu CHOH CH2 CH2 CH2CH2S(O)2iPr 351A tBu C(Me)OH CH2 CH2 CH2CH2S(O)2iPr352A tBu C(O) CH(Me) CH2 CH2CH2S(O)2iPr 353A tBu CHOH CH(Me) CH2CH2CH2S(O)2iPr 354A tBu C(Me)OH CH(Me) CH2 CH2CH2S(O)2iPr 355A tBu C(O)CH2 CH2 CH2CH2S(O)iPr 356A tBu CHOH CH2 CH2 CH2CH2S(O)iPr 357A tBuC(Me)OH CH2 CH2 CH2CH2S(O)iPr 358A tBu C(O) CH(Me) CH2 CH2CH2S(O)iPr359A tBu CHOH CH(Me) CH2 CH2CH2S(O)iPr 360A tBu C(Me)OH CH(Me) CH2CH2CH2S(O)iPr 361A tBu C(O) CH2 CH2 CH2S(O)2tBu 362A tBu CHOH CH2 CH2CH2S(O)2tBu 363A tBu C(Me)OH CH2 CH2 CH2S(O)2tBu 364A tBu C(O) CH(Me)CH2 CH2S(O)2tBu 365A tBu CHOH CH(Me) CH2 CH2S(O)2tBu 366A tBu C(Me)OHCH(Me) CH2 CH2S(O)2tBu 367A tBu C(O) CH2 CH2 CH2S(O)tBu 368A tBu CHOHCH2 CH2 CH2S(O)tBu 369A tBu C(Me)OH CH2 CH2 CH2S(O)tBu 370A tBu C(O)CH(Me) CH2 CH2S(O)tBu 371A tBu CHOH CH(Me) CH2 CH2S(O)tBu 372A tBuC(Me)OH CH(Me) CH2 CH2S(O)tBu 373A tBu C(O) CH2 CH2 CH2CH2S(O)2tBu 374AtBu CHOH CH2 CH2 CH2CH2S(O)2tBu 375A tBu C(Me)OH CH2 CH2 CH2CH2S(O)2tBu376A tBu C(O) CH(Me) CH2 CH2CH2S(O)2tBu 377A tBu CHOH CH(Me) CH2CH2CH2S(O)2tBu 378A tBu C(Me)OH CH(Me) CH2 CH2CH2S(O)2tBu 379A tBu C(O)CH2 CH2 CH2CH2S(O)tBu 380A tBu CHOH CH2 CH2 CH2CH2S(O)tBu 381A tBuC(Me)OH CH2 CH2 CH2CH2S(O)tBu 382A tBu C(O) CH(Me) CH2 CH2CH2S(O)tBu383A tBu CHOH CH(Me) CH2 CH2CH2S(O)tBu 384A tBu C(Me)OH CH(Me) CH2CH2CH2S(O)tBu 385A tBu C(O) CH2 CH2 CH2CH2S(O)2NH2 386A tBu CHOH CH2 CH2CH2CH2S(O)2NH2 387A tBu C(Me)OH CH2 CH2 CH2CH2S(O)2NH2 388A tBu C(O)CH(Me) CH2 CH2CH2S(O)2NH2 389A tBu CHOH CH(Me) CH2 CH2CH2S(O)2NH2 390AtBu C(Me)OH CH(Me) CH2 CH2CH2S(O)2NH2 391A tBu C(O) CH2 CH2CH2CH2S(O)NH2 392A tBu CHOH CH2 CH2 CH2CH2S(O)NH2 393A tBu C(Me)OH CH2CH2 CH2CH2S(O)NH2 394A tBu C(O) CH(Me) CH2 CH2CH2S(O)NH2 395A tBu CHOHCH(Me) CH2 CH2CH2S(O)NH2 396A tBu C(Me)OH CH(Me) CH2 CH2CH2S(O)NH2 397AtBu C(O) CH2 CH2 CH2CH2S(O)2NMe2 398A tBu CHOH CH2 CH2 CH2CH2S(O)2NMe2399A tBu C(Me)OH CH2 CH2 CH2CH2S(O)2NMe2 400A tBu C(O) CH(Me) CH2CH2CH2S(O)2NMe2 401A tBu CHOH CH(Me) CH2 CH2CH2S(O)2NMe2 402A tBuC(Me)OH CH(Me) CH2 CH2CH2S(O)2NMe2 403A tBu C(O) CH2 CH2 CH2CH2S(O)NMe2404A tBu CHOH CH2 CH2 CH2CH2S(O)NMe2 405A tBu C(Me)OH CH2 CH2CH2CH2S(O)NMe2 406A tBu C(O) CH(Me) CH2 CH2CH2S(O)NMe2 407A tBu CHOHCH(Me) CH2 CH2CH2S(O)NMe2 408A tBu C(Me)OH CH(Me) CH2 CH2CH2S(O)NMe2409A tBu C(O) CH2 CH2 C(O)CH2S(O)2Me 410A tBu CHOH CH2 CH2C(O)CH2S(O)2Me 411A tBu C(Me)OH CH2 CH2 C(O)CH2S(O)2Me 412A tBu C(O)CH(Me) CH2 C(O)CH2S(O)2Me 413A tBu CHOH CH(Me) CH2 C(O)CH2S(O)2Me 414AtBu C(Me)OH CH(Me) CH2 C(O)CH2S(O)2Me 415A tBu C(O) CH2 CH2C(O)CH2S(O)Me 416A tBu CHOH CH2 CH2 C(O)CH2S(O)Me 417A tBu C(Me)OH CH2CH2 C(O)CH2S(O)Me 418A tBu C(O) CH(Me) CH2 C(O)CH2S(O)Me 419A tBu CHOHCH(Me) CH2 C(O)CH2S(O)Me 420A tBu C(Me)OH CH(Me) CH2 C(O)CH2S(O)Me 421AtBu C(O) CH2 CH2 C(O)CH2CH2S(O)2Me 422A tBu CHOH CH2 CH2C(O)CH2CH2S(O)2Me 423A tBu C(Me)OH CH2 CH2 C(O)CH2CH2S(O)2Me 424A tBuC(O) CH(Me) CH2 C(O)CH2CH2S(O)2Me 425A tBu CHOH CH(Me) CH2C(O)CH2CH2S(O)2Me 426A tBu C(Me)OH CH(Me) CH2 C(O)CH2CH2S(O)2Me 427A tBuC(O) CH2 CH2 C(O)CH2CH2S(O)Me 428A tBu CHOH CH2 CH2 C(O)CH2CH2S(O)Me429A tBu C(Me)OH CH2 CH2 C(O)CH2CH2S(O)Me 430A tBu C(O) CH(Me) CH2C(O)CH2CH2S(O)Me 431A tBu CHOH CH(Me) CH2 C(O)CH2CH2S(O)Me 432A tBuC(Me)OH CH(Me) CH2 C(O)CH2CH2S(O)Me 433A tBu C(O) CH2 CH2CH2CH2CH2S(O)2NH2 434A tBu CHOH CH2 CH2 CH2CH2CH2S(O)2NH2 435A tBuC(Me)OH CH2 CH2 CH2CH2CH2S(O)2NH2 436A tBu C(O) CH(Me) CH2CH2CH2CH2S(O)2NH2 437A tBu CHOH CH(Me) CH2 CH2CH2CH2S(O)2NH2 438A tBuC(Me)OH CH(Me) CH2 CH2CH2CH2S(O)2NH2 439A tBu C(O) CH2 CH2CH2CH2CH2S(O)NH2 440A tBu CHOH CH2 CH2 CH2CH2CH2S(O)NH2 441A tBu C(Me)OHCH2 CH2 CH2CH2CH2S(O)NH2 442A tBu C(O) CH(Me) CH2 CH2CH2CH2S(O)NH2 443AtBu CHOH CH(Me) CH2 CH2CH2CH2S(O)NH2 444A tBu C(Me)OH CH(Me) CH2CH2CH2CH2S(O)NH2 445A tBu C(O) CH2 CH2 1,3,4-oxadiazolin-2-one-5-yl 446AtBu CHOH CH2 CH2 1,3,4-oxadiazolin-2-one-5-yl 447A tBu C(Me)OH CH2 CH21,3,4-oxadiazolin-2-one-5-yl 448A tBu C(O) CH(Me) CH21,3,4-oxadiazolin-2-one-5-yl 449A tBu CHOH CH(Me) CH21,3,4-oxadiazolin-2-one-5-yl 450A tBu C(Me)OH CH(Me) CH21,3,4-oxadiazolin-2-one-5-yl 451A tBu C(O) CH2 CH21,3,4-oxadiazolin-2-thione- 5-yl 452A tBu CHOH CH2 CH21,3,4-oxadiazolin-2-thione- 5-yl 453A tBu C(Me)OH CH2 CH21,3,4-oxadiazolin-2-thione- 5-yl 454A tBu C(O) CH(Me) CH21,3,4-oxadiazolin-2-thione- 5-yl 455A tBu CHOH CH(Me) CH21,3,4-oxadiazolin-2-thione- 5-yl 456A tBu C(Me)OH CH(Me) CH21,3,4-oxadiazolin-2-thione- 5-yl 457A tBu C(O) CH2 CH2imidazolidine-2,4-dione-5-yl 458A tBu CHOH CH2 CH2imidazolidine-2,4-dione-5-yl 459A tBu C(Me)OH CH2 CH2imidazolidine-2,4-dione-5-yl 460A tBu C(O) CH(Me) CH2imidazolidine-2,4-dione-5-yl 461A tBu CHOH CH(Me) CH2imidazolidine-2,4-dione-5-yl 462A tBu C(Me)OH CH(Me) CH2imidazolidine-2,4-dione-5-yl 463A tBu C(O) CH2 CH2 isoxazol-3-ol-5-yl464A tBu CHOH CH2 CH2 isoxazol-3-ol-5-yl 465A tBu C(Me)OH CH2 CH2isoxazol-3-ol-5-yl 466A tBu C(O) CH(Me) CH2 isoxazol-3-ol-5-yl 467A tBuCHOH CH(Me) CH2 isoxazol-3-ol-5-yl 468A tBu C(Me)OH CH(Me) CH2isoxazol-3-ol-5-yl

Among other preferred compounds of the invention are also thoserepresented by the formula:

and pharmaceutically acceptable salts thereof;wherein;

said compound is selected from a compound code numbered 1B thru 81B,with each compound having the specific selection of substituents R_(B),R_(C), L₁, L₂, and L₃ shown

in the row following the compound code number, as set out in thefollowing Table 3:

TABLE 3 R_(B) L₃ L₂ L₁ R_(C) 1B tBu C(O) CH2 O —C(O)NH—CH₂—C(O)OH 2B tBuCHOH CH2 O —C(O)NH—CH₂—C(O)OH 3B tBu C(Me)OH CH2 O —C(O)NH—CH₂—C(O)OH 4BtBu C(O) CH(Me) O —C(O)NH—CH₂—C(O)OH 5B tBu CHOH CH(Me) O—C(O)NH—CH₂—C(O)OH 6B tBu C(Me)OH CH(Me) O —C(O)NH—CH₂—C(O)OH 7B tBuC(O) CH2 O —C(O)NH—CH(Me)-C(O)OH 8B tBu CHOH CH2 O —C(O)NH—CH(Me)-C(O)OH9B tBu C(Me)OH CH2 O —C(O)NH—CH(Me)-C(O)OH 10B tBu C(O) CH(Me) O—C(O)NH—CH(Me)-C(O)OH 11B tBu CHOH CH(Me) O —C(O)NH—CH(Me)-C(O)OH 12BtBu C(Me)OH CH(Me) O —C(O)NH—CH(Me)-C(O)OH 13B tBu C(O) CH2 O—C(O)NH—CH(Et)-C(O)OH 14B tBu CHOH CH2 O —C(O)NH—CH(Et)-C(O)OH 15B tBuC(Me)OH CH2 O —C(O)NH—CH(Et)-C(O)OH 16B tBu C(O) CH(Me) O—C(O)NH—CH(Et)-C(O)OH 17B tBu CHOH CH(Me) O —C(O)NH—CH(Et)-C(O)OH 18BtBu C(Me)OH CH(Me) O —C(O)NH—CH(Et)-C(O)OH 19B tBu C(O) CH2 O—C(O)NH—C(Me)₂-C(O)OH 20B tBu CHOH CH2 O —C(O)NH—C(Me)₂-C(O)OH 21B tBuC(Me)OH CH2 O —C(O)NH—C(Me)₂-C(O)OH 22B tBu C(O) CH(Me) O—C(O)NH—C(Me)₂-C(O)OH 23B tBu CHOH CH(Me) O —C(O)NH—C(Me)₂-C(O)OH 24BtBu C(Me)OH CH(Me) O —C(O)NH—C(Me)₂-C(O)OH 25B tBu C(O) CH2 O—C(O)NH—CMe(Et)-C(O)OH 26B tBu CHOH CH2 O —C(O)NH—CMe(Et)-C(O)OH 27B tBuC(Me)OH CH2 O —C(O)NH—CMe(Et)-C(O)OH 28B tBu C(O) CH(Me) O—C(O)NH—CMe(Et)-C(O)OH 29B tBu CHOH CH(Me) O —C(O)NH—CMe(Et)-C(O)OH 30BtBu C(Me)OH CH(Me) O —C(O)NH—CMe(Et)-C(O)OH 31B tBu C(O) CH2 O—C(O)NH—CH(F)—C(O)OH 32B tBu CHOH CH2 O —C(O)NH—CH(F)—C(O)OH 33B tBuC(Me)OH CH2 O —C(O)NH—CH(F)—C(O)OH 34B tBu C(O) CH(Me) O—C(O)NH—CH(F)—C(O)OH 35B tBu CHOH CH(Me) O —C(O)NH—CH(F)—C(O)OH 36B tBuC(Me)OH CH(Me) O —C(O)NH—CH(F)—C(O)OH 37B tBu C(O) CH2 O—C(O)NH—CH(CF₃)—C(O)OH 38B tBu CHOH CH2 O —C(O)NH—CH(CF₃)—C(O)OH 39B tBuC(Me)OH CH2 O —C(O)NH—CH(CF₃)—C(O)OH 40B tBu C(O) CH(Me) O—C(O)NH—CH(CF₃)—C(O)OH 41B tBu CHOH CH(Me) O —C(O)NH—CH(CF₃)—C(O)OH 42BtBu C(Me)OH CH(Me) O —C(O)NH—CH(CF₃)—C(O)OH 43B tBu C(O) CH2 O—C(O)NH—CH(OH)—C(O)OH 44B tBu CHOH CH2 O —C(O)NH—CH(OH)—C(O)OH 45B tBuC(Me)OH CH2 O —C(O)NH—CH(OH)—C(O)OH 46B tBu C(O) CH(Me) O—C(O)NH—CH(OH)—C(O)OH 47B tBu CHOH CH(Me) O —C(O)NH—CH(OH)—C(O)OH 48BtBu C(Me)OH CH(Me) O —C(O)NH—CH(OH)—C(O)OH 49B tBu C(O) CH2 O—C(O)NH—CH(cyclopropyl)-C(O)OH 50B tBu CHOH CH2 O—C(O)NH—CH(cyclopropyl)-C(O)OH 51B tBu C(Me)OH CH2 O—C(O)NH—CH(cyclopropyl)-C(O)OH 52B tBu C(O) CH(Me) O—C(O)NH—CH(cyclopropyl)-C(O)OH 53B tBu CHOH CH(Me) O—C(O)NH—CH(cyclopropyl)-C(O)OH 54B tBu C(Me)OH CH(Me) O—C(O)NH—CH(cyclopropyl)-C(O)OH 55B tBu C(O) CH2 O —C(O)NH—CH(Me)-C(O)OH56B tBu CHOH CH2 O —C(O)NH—CH(Me)-C(O)OH 57B tBu C(Me)OH CH2 O—C(O)NH—CH(Me)-C(O)OH 58B tBu C(O) CH(Me) O —C(O)NH—CH(Me)-C(O)OH 59BtBu CHOH CH(Me) O —C(O)NH—CH(Me)-C(O)OH 60B tBu C(Me)OH CH(Me) O—C(O)NH—CH(Me)-C(O)OH 61B tBu C(O) CH2 O —C(O)NH—C(Me)₂-C(O)OH 62B tBuCHOH CH2 O —C(O)NH—C(Me)₂-C(O)OH 63B tBu C(Me)OH CH2 O—C(O)NH—C(Me)₂-C(O)OH 64B tBu C(O) CH(Me) O —C(O)NH—C(Me)₂-C(O)OH 65BtBu CHOH CH(Me) O —C(O)NH—C(Me)₂-C(O)OH 66B tBu C(Me)OH CH(Me) O—C(O)NH—C(Me)₂-C(O)OH 67B tBu C(O) CH2 O —C(O)NH—CF(Me)-C(O)OH 68B tBuCHOH CH2 O —C(O)NH—CF(Me)-C(O)OH 69B tBu C(Me)OH CH2 O—C(O)NH—CF(Me)-C(O)OH 70B tBu C(O) CH(Me) O —C(O)NH—CF(Me)-C(O)OH 71BtBu CHOH CH(Me) O —C(O)NH—CF(Me)-C(O)OH 72B tBu C(Me)OH CH(Me) O—C(O)NH—CF(Me)-C(O)OH 73B tBu C(O) CH2 O —C(O)NH—C(Me)(CF₃)—C(O)OH 74BtBu CHOH CH2 O —C(O)NH—C(Me)(CF₃)—C(O)OH 75B tBu C(Me)OH CH2 O—C(O)NH—C(Me)(CF₃)—C(O)OH 76B tBu C(O) CH(Me) O—C(O)NH—C(Me)(CF₃)—C(O)OH 77B tBu CHOH CH(Me) O—C(O)NH—C(Me)(CF₃)—C(O)OH 78B tBu C(Me)OH CH(Me) O—C(O)NH—C(Me)(CF₃)—C(O)OH 79B tBu C(O) CH2 O —C(O)NH—C(Me)(OH)—C(O)OH80B tBu CHOH CH2 O —C(O)NH—C(Me)(OH)—C(O)OH 81B tBu C(Me)OH CH2 O—C(O)NH—C(Me)(OH)—C(O)OH 82B tBu C(O) CH(Me) O —C(O)NH—C(Me)(OH)—C(O)OH83B tBu CHOH CH(Me) O —C(O)NH—C(Me)(OH)—C(O)OH 84B tBu C(Me)OH CH(Me) O—C(O)NH—C(Me)(OH)—C(O)OH 85B tBu C(O) CH2 O—C(O)NH—C(Me)(cyclopropyl)CO₂H 86B tBu CHOH CH2 O—C(O)NH—C(Me)(cyclopropyl)CO₂H 87B tBu C(Me)OH CH2 O—C(O)NH—C(Me)(cyclopropyl)CO₂H 88B tBu C(O) CH(Me) O—C(O)NH—C(Me)(cyclopropyl)CO₂H 89B tBu CHOH CH(Me) O—C(O)NH—C(Me)(cyclopropyl)CO₂H 90B tBu C(Me)OH CH(Me) O—C(O)NH—C(Me)(cyclopropyl)CO₂H 91B tBu C(O) CH2 O —C(O)NMe-CH₂—C(O)OH92B tBu CHOH CH2 O —C(O)NMe-CH₂—C(O)OH 93B tBu C(Me)OH CH2 O—C(O)NMe-CH₂—C(O)OH 94B tBu C(O) CH(Me) O —C(O)NMe-CH₂—C(O)OH 95B tBuCHOH CH(Me) O —C(O)NMe-CH₂—C(O)OH 96B tBu C(Me)OH CH(Me) O—C(O)NMe-CH₂—C(O)OH 97B tBu C(O) CH2 O —C(O)NMe-CH(Me)-C(O)OH 98B tBuCHOH CH2 O —C(O)NMe-CH(Me)-C(O)OH 99B tBu C(Me)OH CH2 O—C(O)NMe-CH(Me)-C(O)OH 100B tBu C(O) CH(Me) O —C(O)NMe-CH(Me)-C(O)OH101B tBu CHOH CH(Me) O —C(O)NMe-CH(Me)-C(O)OH 102B tBu C(Me)OH CH(Me) O—C(O)NMe-CH(Me)-C(O)OH 103B tBu C(O) CH2 O —C(O)NMe-CH(F)—C(O)OH 104BtBu CHOH CH2 O —C(O)NMe-CH(F)—C(O)OH 105B tBu C(Me)OH CH2 O—C(O)NMe-CH(F)—C(O)OH 106B tBu C(O) CH(Me) O —C(O)NMe-CH(F)—C(O)OH 107BtBu CHOH CH(Me) O —C(O)NMe-CH(F)—C(O)OH 108B tBu C(Me)OH CH(Me) O—C(O)NMe-CH(F)—C(O)OH 109B tBu C(O) CH2 O —C(O)NMe-CH(CF₃)—C(O)OH 110BtBu CHOH CH2 O —C(O)NMe-CH(CF₃)—C(O)OH 111B tBu C(Me)OH CH2 O—C(O)NMe-CH(CF₃)—C(O)OH 112B tBu C(O) CH(Me) O —C(O)NMe-CH(CF₃)—C(O)OH113B tBu CHOH CH(Me) O —C(O)NMe-CH(CF₃)—C(O)OH 114B tBu C(Me)OH CH(Me) O—C(O)NMe-CH(CF₃)—C(O)OH 115B tBu C(O) CH2 O —C(O)NMe-CH(OH)—C(O)OH 116BtBu CHOH CH2 O —C(O)NMe-CH(OH)—C(O)OH 117B tBu C(Me)OH CH2 O—C(O)NMe-CH(OH)—C(O)OH 118B tBu C(O) CH(Me) O —C(O)NMe-CH(OH)—C(O)OH119B tBu CHOH CH(Me) O —C(O)NMe-CH(OH)—C(O)OH 120B tBu C(Me)OH CH(Me) O—C(O)NMe-CH(OH)—C(O)OH 121B tBu C(O) CH2 O —C(O)NMe-CH(cyclopropyl)-C(O)OH 122B tBu CHOH CH2 O —C(O)NMe-CH(cyclopropyl)- C(O)OH 123B tBuC(Me)OH CH2 O —C(O)NMe-CH(cyclopropyl)- C(O)OH 124B tBu C(O) CH(Me) O—C(O)NMe-CH(cyclopropyl)- C(O)OH 125B tBu CHOH CH(Me) O—C(O)NMe-CH(cyclopropyl)- C(O)OH 126B tBu C(Me)OH CH(Me) O—C(O)NMe-CH(cyclopropyl)- C(O)OH 127B tBu C(O) CH2 O—C(O)NMe-C(Me)₂-C(O)OH 128B tBu CHOH CH2 O —C(O)NMe-C(Me)₂-C(O)OH 129BtBu C(Me)OH CH2 O —C(O)NMe-C(Me)₂-C(O)OH 130B tBu C(O) CH(Me) O—C(O)NMe-C(Me)₂-C(O)OH 131B tBu CHOH CH(Me) O —C(O)NMe-C(Me)₂-C(O)OH132B tBu C(Me)OH CH(Me) O —C(O)NMe-C(Me)₂-C(O)OH 133B tBu C(O) CH2 O—C(O)NMe-CF(Me)-C(O)OH 134B tBu CHOH CH2 O —C(O)NMe-CF(Me)-C(O)OH 135BtBu C(Me)OH CH2 O —C(O)NMe-CF(Me)-C(O)OH 136B tBu C(O) CH(Me) O—C(O)NMe-CF(Me)-C(O)OH 137B tBu CHOH CH(Me) O —C(O)NMe-CF(Me)-C(O)OH138B tBu C(Me)OH CH(Me) O —C(O)NMe-CF(Me)-C(O)OH 139B tBu C(O) CH2 O—C(O)NMe-C(Me)(CF₃)—C(O)OH 140B tBu CHOH CH2 O—C(O)NMe-C(Me)(CF₃)—C(O)OH 141B tBu C(Me)OH CH2 O—C(O)NMe-C(Me)(CF₃)—C(O)OH 142B tBu C(O) CH(Me) O—C(O)NMe-C(Me)(CF₃)—C(O)OH 143B tBu CHOH CH(Me) O—C(O)NMe-C(Me)(CF₃)—C(O)OH 144B tBu C(Me)OH CH(Me) O—C(O)NMe-C(Me)(CF₃)—C(O)OH 145B tBu C(O) CH2 O —C(O)NMe-C(Me)(OH)—C(O)OH146B tBu CHOH CH2 O —C(O)NMe-C(Me)(OH)—C(O)OH 147B tBu C(Me)OH CH2 O—C(O)NMe-C(Me)(OH)—C(O)OH 148B tBu C(O) CH(Me) O—C(O)NMe-C(Me)(OH)—C(O)OH 149B tBu CHOH CH(Me) O—C(O)NMe-C(Me)(OH)—C(O)OH 150B tBu C(Me)OH CH(Me) O—C(O)NMe-C(Me)(OH)—C(O)OH 151B tBu C(O) CH2 O—C(O)NMe-C(Me)(cyclopropyl)- C(O)OH 152B tBu CHOH CH2 O—C(O)NMe-C(Me)(cyclopropyl)- C(O)OH 153B tBu C(Me)OH CH2 O—C(O)NMe-C(Me)(cyclopropyl)- C(O)OH 154B tBu C(O) CH(Me) O—C(O)NMe-C(Me)(cyclopropyl)- C(O)OH 155B tBu CHOH CH(Me) O—C(O)NMe-C(Me)(cyclopropyl)- C(O)OH 156B tBu C(Me)OH CH(Me) O—C(O)NMe-C(Me)(cyclopropyl)- C(O)OH 157B tBu C(O) CH2 O—C(O)—N(Me)-5-tetrazolyl 158B tBu CHOH CH2 O —C(O)—N(Me)-5-tetrazolyl159B tBu C(Me)OH CH2 O —C(O)—N(Me)-5-tetrazolyl 160B tBu C(O) CH(Me) O—C(O)—N(Me)-5-tetrazolyl 161B tBu CHOH CH(Me) O —C(O)—N(Me)-5-tetrazolyl162B tBu C(Me)OH CH(Me) O —C(O)—N(Me)-5-tetrazolyl

Among other preferred compounds of the invention are also thoserepresented by the formula:

and pharmaceutically acceptable salts thereof;wherein;

said compound is selected from a compound code numbered 1C thru 162C,with each compound having the specific selection of substituents R_(B),R_(C), L₁, L₂, and L₃ shown

in the row following the compound code number, as set out in thefollowing Table 4:

TABLE 4 R_(B) L₃ L₂ L₁ R_(C) 1C tBu C(O) CH2 CH2 —C(O)NH—CH₂—C(O)OH 2CtBu CHOH CH2 CH2 —C(O)NH—CH₂—C(O)OH 3C tBu C(Me)OH CH2 CH2—C(O)NH—CH₂—C(O)OH 4C tBu C(O) CH(Me) CH2 —C(O)NH—CH₂—C(O)OH 5C tBu CHOHCH(Me) CH2 —C(O)NH—CH₂—C(O)OH 6C tBu C(Me)OH CH(Me) CH2—C(O)NH—CH₂—C(O)OH 7C tBu C(O) CH2 CH2 —C(O)NH—CH(Me)-C(O)OH 8C tBu CHOHCH2 CH2 —C(O)NH—CH(Me)-C(O)OH 9C tBu C(Me)OH CH2 CH2—C(O)NH—CH(Me)-C(O)OH 10C tBu C(O) CH(Me) CH2 —C(O)NH—CH(Me)-C(O)OH 11CtBu CHOH CH(Me) CH2 —C(O)NH—CH(Me)-C(O)OH 12C tBu C(Me)OH CH(Me) CH2—C(O)NH—CH(Me)-C(O)OH 13C tBu C(O) CH2 CH2 —C(O)NH—CH(Et)-C(O)OH 14C tBuCHOH CH2 CH2 —C(O)NH—CH(Et)-C(O)OH 15C tBu C(Me)OH CH2 CH2—C(O)NH—CH(Et)-C(O)OH 16C tBu C(O) CH(Me) CH2 —C(O)NH—CH(Et)-C(O)OH 17CtBu CHOH CH(Me) CH2 —C(O)NH—CH(Et)-C(O)OH 18C tBu C(Me)OH CH(Me) CH2—C(O)NH—CH(Et)-C(O)OH 19C tBu C(O) CH2 CH2 —C(O)NH—C(Me)₂-C(O)OH 20C tBuCHOH CH2 CH2 —C(O)NH—C(Me)₂-C(O)OH 21C tBu C(Me)OH CH2 CH2—C(O)NH—C(Me)₂-C(O)OH 22C tBu C(O) CH(Me) CH2 —C(O)NH—C(Me)₂-C(O)OH 23CtBu CHOH CH(Me) CH2 —C(O)NH—C(Me)₂-C(O)OH 24C tBu C(Me)OH CH(Me) CH2—C(O)NH—C(Me)₂-C(O)OH 25C tBu C(O) CH2 CH2 —C(O)NH—CMe(Et)-C(O)OH 26CtBu CHOH CH2 CH2 —C(O)NH—CMe(Et)-C(O)OH 27C tBu C(Me)OH CH2 CH2—C(O)NH—CMe(Et)-C(O)OH 28C tBu C(O) CH(Me) CH2 —C(O)NH—CMe(Et)-C(O)OH29C tBu CHOH CH(Me) CH2 —C(O)NH—CMe(Et)-C(O)OH 30C tBu C(Me)OH CH(Me)CH2 —C(O)NH—CMe(Et)-C(O)OH 31C tBu C(O) CH2 CH2 —C(O)NH—CH(F)—C(O)OH 32CtBu CHOH CH2 CH2 —C(O)NH—CH(F)—C(O)OH 33C tBu C(Me)OH CH2 CH2—C(O)NH—CH(F)—C(O)OH 34C tBu C(O) CH(Me) CH2 —C(O)NH—CH(F)—C(O)OH 35CtBu CHOH CH(Me) CH2 —C(O)NH—CH(F)—C(O)OH 36C tBu C(Me)OH CH(Me) CH2—C(O)NH—CH(F)—C(O)OH 37C tBu C(O) CH2 CH2 —C(O)NH—CH(CF₃)—C(O)OH 38C tBuCHOH CH2 CH2 —C(O)NH—CH(CF₃)—C(O)OH 39C tBu C(Me)OH CH2 CH2—C(O)NH—CH(CF₃)—C(O)OH 40C tBu C(O) CH(Me) CH2 —C(O)NH—CH(CF₃)—C(O)OH41C tBu CHOH CH(Me) CH2 —C(O)NH—CH(CF₃)—C(O)OH 42C tBu C(Me)OH CH(Me)CH2 —C(O)NH—CH(CF₃)—C(O)OH 43C tBu C(O) CH2 CH2 —C(O)NH—CH(OH)—C(O)OH44C tBu CHOH CH2 CH2 —C(O)NH—CH(OH)—C(O)OH 45C tBu C(Me)OH CH2 CH2—C(O)NH—CH(OH)—C(O)OH 46C tBu C(O) CH(Me) CH2 —C(O)NH—CH(OH)—C(O)OH 47CtBu CHOH CH(Me) CH2 —C(O)NH—CH(OH)—C(O)OH 48C tBu C(Me)OH CH(Me) CH2—C(O)NH—CH(OH)—C(O)OH 49C tBu C(O) CH2 CH2—C(O)NH—CH(cyclopropyl)-C(O)OH 50C tBu CHOH CH2 CH2—C(O)NH—CH(cyclopropyl)-C(O)OH 51C tBu C(Me)OH CH2 CH2—C(O)NH—CH(cyclopropyl)-C(O)OH 52C tBu C(O) CH(Me) CH2—C(O)NH—CH(cyclopropyl)-C(O)OH 53C tBu CHOH CH(Me) CH2—C(O)NH—CH(cyclopropyl)-C(O)OH 54C tBu C(Me)OH CH(Me) CH2—C(O)NH—CH(cyclopropyl)-C(O)OH 55C tBu C(O) CH2 CH2—C(O)NH—CH(Me)-C(O)OH 56C tBu CHOH CH2 CH2 —C(O)NH—CH(Me)-C(O)OH 57C tBuC(Me)OH CH2 CH2 —C(O)NH—CH(Me)-C(O)OH 58C tBu C(O) CH(Me) CH2—C(O)NH—CH(Me)-C(O)OH 59C tBu CHOH CH(Me) CH2 —C(O)NH—CH(Me)-C(O)OH 60CtBu C(Me)OH CH(Me) CH2 —C(O)NH—CH(Me)-C(O)OH 61C tBu C(O) CH2 CH2—C(O)NH—C(Me)₂-C(O)OH 62C tBu CHOH CH2 CH2 —C(O)NH—C(Me)₂-C(O)OH 63C tBuC(Me)OH CH2 CH2 —C(O)NH—C(Me)₂-C(O)OH 64C tBu C(O) CH(Me) CH2—C(O)NH—C(Me)₂-C(O)OH 65C tBu CHOH CH(Me) CH2 —C(O)NH—C(Me)₂-C(O)OH 66CtBu C(Me)OH CH(Me) CH2 —C(O)NH—C(Me)₂-C(O)OH 67C tBu C(O) CH2 CH2—C(O)NH—CF(Me)-C(O)OH 68C tBu CHOH CH2 CH2 —C(O)NH—CF(Me)-C(O)OH 69C tBuC(Me)OH CH2 CH2 —C(O)NH—CF(Me)-C(O)OH 70C tBu C(O) CH(Me) CH2—C(O)NH—CF(Me)-C(O)OH 71C tBu CHOH CH(Me) CH2 —C(O)NH—CF(Me)-C(O)OH 72CtBu C(Me)OH CH(Me) CH2 —C(O)NH—CF(Me)-C(O)OH 73C tBu C(O) CH2 CH2—C(O)NH—C(Me)(CF₃)—C(O)OH 74C tBu CHOH CH2 CH2 —C(O)NH—C(Me)(CF₃)—C(O)OH75C tBu C(Me)OH CH2 CH2 —C(O)NH—C(Me)(CF₃)—C(O)OH 76C tBu C(O) CH(Me)CH2 —C(O)NH—C(Me)(CF₃)—C(O)OH 77C tBu CHOH CH(Me) CH2—C(O)NH—C(Me)(CF₃)—C(O)OH 78C tBu C(Me)OH CH(Me) CH2—C(O)NH—C(Me)(CF₃)—C(O)OH 79C tBu C(O) CH2 CH2 —C(O)NH—C(Me)(OH)—C(O)OH80C tBu CHOH CH2 CH2 —C(O)NH—C(Me)(OH)—C(O)OH 81C tBu C(Me)OH CH2 CH2—C(O)NH—C(Me)(OH)—C(O)OH 82C tBu C(O) CH(Me) CH2—C(O)NH—C(Me)(OH)—C(O)OH 83C tBu CHOH CH(Me) CH2—C(O)NH—C(Me)(OH)—C(O)OH 84C tBu C(Me)OH CH(Me) CH2—C(O)NH—C(Me)(OH)—C(O)OH 85C tBu C(O) CH2 CH2—C(O)NH—C(Me)(cyclopropyl)CO₂H 86C tBu CHOH CH2 CH2—C(O)NH—C(Me)(cyclopropyl)CO₂H 87C tBu C(Me)OH CH2 CH2—C(O)NH—C(Me)(cyclopropyl)CO₂H 88C tBu C(O) CH(Me) CH2—C(O)NH—C(Me)(cyclopropyl)CO₂H 89C tBu CHOH CH(Me) CH2—C(O)NH—C(Me)(cyclopropyl)CO₂H 90C tBu C(Me)OH CH(Me) CH2—C(O)NH—C(Me)(cyclopropyl)CO₂H 91C tBu C(O) CH2 CH2 —C(O)NMe-CH₂—C(O)OH92C tBu CHOH CH2 CH2 —C(O)NMe-CH₂—C(O)OH 93C tBu C(Me)OH CH2 CH2—C(O)NMe-CH₂—C(O)OH 94C tBu C(O) CH(Me) CH2 —C(O)NMe-CH₂—C(O)OH 95C tBuCHOH CH(Me) CH2 —C(O)NMe-CH₂—C(O)OH 96C tBu C(Me)OH CH(Me) CH2—C(O)NMe-CH₂—C(O)OH 97C tBu C(O) CH2 CH2 —C(O)NMe-CH(Me)-C(O)OH 98C tBuCHOH CH2 CH2 —C(O)NMe-CH(Me)-C(O)OH 99C tBu C(Me)OH CH2 CH2—C(O)NMe-CH(Me)-C(O)OH 100C tBu C(O) CH(Me) CH2 —C(O)NMe-CH(Me)-C(O)OH101C tBu CHOH CH(Me) CH2 —C(O)NMe-CH(Me)-C(O)OH 102C tBu C(Me)OH CH(Me)CH2 —C(O)NMe-CH(Me)-C(O)OH 103C tBu C(O) CH2 CH2 —C(O)NMe-CH(F)—C(O)OH104C tBu CHOH CH2 CH2 —C(O)NMe-CH(F)—C(O)OH 105C tBu C(Me)OH CH2 CH2—C(O)NMe-CH(F)—C(O)OH 106C tBu C(O) CH(Me) CH2 —C(O)NMe-CH(F)—C(O)OH107C tBu CHOH CH(Me) CH2 —C(O)NMe-CH(F)—C(O)OH 108C tBu C(Me)OH CH(Me)CH2 —C(O)NMe-CH(F)—C(O)OH 109C tBu C(O) CH2 CH2 —C(O)NMe-CH(CF₃)—C(O)OH110C tBu CHOH CH2 CH2 —C(O)NMe-CH(CF₃)—C(O)OH 111C tBu C(Me)OH CH2 CH2—C(O)NMe-CH(CF₃)—C(O)OH 112C tBu C(O) CH(Me) CH2 —C(O)NMe-CH(CF₃)—C(O)OH113C tBu CHOH CH(Me) CH2 —C(O)NMe-CH(CF₃)—C(O)OH 114C tBu C(Me)OH CH(Me)CH2 —C(O)NMe-CH(CF₃)—C(O)OH 115C tBu C(O) CH2 CH2 —C(O)NMe-CH(OH)—C(O)OH116C tBu CHOH CH2 CH2 —C(O)NMe-CH(OH)—C(O)OH 117C tBu C(Me)OH CH2 CH2—C(O)NMe-CH(OH)—C(O)OH 118C tBu C(O) CH(Me) CH2 —C(O)NMe-CH(OH)—C(O)OH119C tBu CHOH CH(Me) CH2 —C(O)NMe-CH(OH)—C(O)OH 120C tBu C(Me)OH CH(Me)CH2 —C(O)NMe-CH(OH)—C(O)OH 121C tBu C(O) CH2 CH2—C(O)NMe-CH(cyclopropyl)-C(O)OH 122C tBu CHOH CH2 CH2—C(O)NMe-CH(cyclopropyl)-C(O)OH 123C tBu C(Me)OH CH2 CH2—C(O)NMe-CH(cyclopropyl)-C(O)OH 124C tBu C(O) CH(Me) CH2—C(O)NMe-CH(cyclopropyl)-C(O)OH 125C tBu CHOH CH(Me) CH2—C(O)NMe-CH(cyclopropyl)-C(O)OH 126C tBu C(Me)OH CH(Me) CH2—C(O)NMe-CH(cyclopropyl)-C(O)OH 127C tBu C(O) CH2 CH2—C(O)NMe-C(Me)₂-C(O)OH 128C tBu CHOH CH2 CH2 —C(O)NMe-C(Me)₂-C(O)OH 129CtBu C(Me)OH CH2 CH2 —C(O)NMe-C(Me)₂-C(O)OH 130C tBu C(O) CH(Me) CH2—C(O)NMe-C(Me)₂-C(O)OH 131C tBu CHOH CH(Me) CH2 —C(O)NMe-C(Me)₂-C(O)OH132C tBu C(Me)OH CH(Me) CH2 —C(O)NMe-C(Me)₂-C(O)OH 133C tBu C(O) CH2 CH2—C(O)NMe-CF(Me)-C(O)OH 134C tBu CHOH CH2 CH2 —C(O)NMe-CF(Me)-C(O)OH 135CtBu C(Me)OH CH2 CH2 —C(O)NMe-CF(Me)-C(O)OH 136C tBu C(O) CH(Me) CH2—C(O)NMe-CF(Me)-C(O)OH 137C tBu CHOH CH(Me) CH2 —C(O)NMe-CF(Me)-C(O)OH138C tBu C(Me)OH CH(Me) CH2 —C(O)NMe-CF(Me)-C(O)OH 139C tBu C(O) CH2 CH2—C(O)NMe-C(Me)(CF₃)—C(O)OH 140C tBu CHOH CH2 CH2—C(O)NMe-C(Me)(CF₃)—C(O)OH 141C tBu C(Me)OH CH2 CH2—C(O)NMe-C(Me)(CF₃)—C(O)OH 142C tBu C(O) CH(Me) CH2—C(O)NMe-C(Me)(CF₃)—C(O)OH 143C tBu CHOH CH(Me) CH2—C(O)NMe-C(Me)(CF₃)—C(O)OH 144C tBu C(Me)OH CH(Me) CH2—C(O)NMe-C(Me)(CF₃)—C(O)OH 145C tBu C(O) CH2 CH2—C(O)NMe-C(Me)(OH)—C(O)OH 146C tBu CHOH CH2 CH2—C(O)NMe-C(Me)(OH)—C(O)OH 147C tBu C(Me)OH CH2 CH2—C(O)NMe-C(Me)(OH)—C(O)OH 148C tBu C(O) CH(Me) CH2—C(O)NMe-C(Me)(OH)—C(O)OH 149C tBu CHOH CH(Me) CH2—C(O)NMe-C(Me)(OH)—C(O)OH 150C tBu C(Me)OH CH(Me) CH2—C(O)NMe-C(Me)(OH)—C(O)OH 151C tBu C(O) CH2 CH2—C(O)NMe-C(Me)(cyclopropyl)-C(O)OH 152C tBu CHOH CH2 CH2—C(O)NMe-C(Me)(cyclopropyl)-C(O)OH 153C tBu C(Me)OH CH2 CH2—C(O)NMe-C(Me)(cyclopropyl)-C(O)OH 154C tBu C(O) CH(Me) CH2—C(O)NMe-C(Me)(cyclopropyl)-C(O)OH 155C tBu CHOH CH(Me) CH2—C(O)NMe-C(Me)(cyclopropyl)-C(O)OH 156C tBu C(Me)OH CH(Me) CH2—C(O)NMe-C(Me)(cyclopropyl)-C(O)OH 157C tBu C(O) CH2 CH2—C(O)—N(Me)-5-tetrazolyl 158C tBu CHOH CH2 CH2 —C(O)—N(Me)-5-tetrazolyl159C tBu C(Me)OH CH2 CH2 —C(O)—N(Me)-5-tetrazolyl 160C tBu C(O) CH(Me)CH2 —C(O)—N(Me)-5-tetrazolyl 161C tBu CHOH CH(Me) CH2—C(O)—N(Me)-5-tetrazolyl 162C tBu C(Me)OH CH(Me) CH2—C(O)—N(Me)-5-tetrazolyl

Method of Making the Compounds of the Invention:

Compounds of the invention represented by formula (I) may be prepared bythe methods set out below. It will be understood by one skilled in thechemical arts that the reactants may be varied to analogous molecules toprovide desired substitutions in the final reaction product.

DEFINITIONS OF SYMBOLS USED IN THE SCHEMES

-   -   (PhO)2P(O)N3—diphenyl phosphorus azide    -   BBr3—boron tribromide    -   BF3-OEt2—boron trifluoride etherate    -   BnBr—benzyl bromide    -   CH3CN —acetonitrile    -   DMAP—4-(dimethylamino)pyridine    -   DMF—N,N-dimethylformamide    -   DMSO—dimethylsulfoxide    -   DPPF—dichloro[1,1′-bis(diphenylphosphino)ferrocene    -   DPPB—1,4-bis(diphenylphosphino)butane    -   EDCI—3-Ethyl-1-[3-(dimethylamino)propyl]carbodiimide        hydrochloride    -   Et3N —triethylamine    -   EtOH—ethanol    -   H2NCH2CO2Me—methyl glycinate    -   HN(OMe)Me—N-methyl-O-methyl hydroxylamine    -   HNMe2—dimethyl amine    -   K2CO3—potassium carbonate    -   KOH—potassium hydroxide    -   LAH—lithium aluminum hydride    -   LiHMDS—lithium hexamethyldisilazide    -   mCPBA—meta-chloroperbenzoic acid    -   MeI—methyl iodide    -   MeOH—methanol    -   NaBH4—sodium borohydride    -   NaH—sodium hydride    -   NaI—sodium iodide    -   NMP—N-methylpyrrolidin-2-one    -   Na—S-R3—sodium alkylmercaptide    -   PBr3—phosphorus tribromide    -   Pd(OAc)2—palladium (II) acetate    -   Pd—C—palladium on carbon    -   pTSA—para-toluenesulfonic acid    -   Pyr—pyridine    -   R2MgBr—alkyl magnesium bromide    -   R3MgBr—alkyl magnesium bromide    -   R5MgBr—alkyl magnesium bromide    -   R2S(O)2NH2—alkylsulfonamide    -   tBuC(O)CH2Br—2-bromopinacolone    -   Tf2O—triflic anhydride    -   TFA—trifluoroacetic acid    -   THF—tetrahydrofuran

Description of the Schemes:

Preparation of diphenyl acid and diphenyl acylaminotetrazole (Scheme 1).

A mixture of 3-substituted-4-hydroxy benzoic acid 1a and methanol istreated with HCl (gas) to yield methyl benzoate ester 1. Methyl benzoateester 1 is reacted with excess alkyl magnesium bromide to producetertiary alcohol 2. Tertiary alcohol 2 is converted to phenol 4 byreaction with O-benzyl-2-substituted phenol 3a and BF3-Et2O.O-benzyl-2-substituted phenol 3a is derived from the reaction of2-substituted phenol 3 with benzylbromide and NaH. Phenol 4 is reactedwith triflic anhydride/pyridine to give triflate 5 which is subjected tomethoxycarbonylation with Pd(OAc)₂, DPPF, CO (689-6895 KPa), methanoland triethylamine in either DMF or DMSO at 80-100° C. to yield methylester 6. DPPB may be used instead of DPPF for the methoxycarbonylationreaction. Methyl ester 6 is subjected to palladium catalyzedhydrogenolysis and alkylated with NaH/pinacolone bromide to give ketone7. Ketone 7 is sequentially reacted with sodium borohydride/MeOH andpotassium hydroxide/EtOH/H2O/80° C. to produce acid 8. Acid 8 is coupledwith EDCI, DMAP and 5-aminotetrazole to give acylamino tetrazole 9. Acid8 is also coupled with EDCI, DMAP and alkylsulfonamide to giveacylsulfonamide 9a.

Preparation of Functionalized Sidechain Analogs (Scheme 2).

Ester 6 is reduced with LAH to give benzyl alcohol 10. Benzyl alcohol 10is converted to benzylic bromide 11 with PBr3 and alklylated with theenolate of pinacolone to afford ketone 12. Ketone 12 is transformed intoketo-ester 14 via Pd—C catalyzed hydrogenolysis, triflate formation withtriflic anhydride/pyridine and palladium catalyzed methoxycarbonylation.Keto-ester 14 is subjected to sodium borohydride reduction and potassiumhydroxide hydrolysis to produce alcohol-acid 15. Alcohol-acid 15 iscoupled with EDCI/Et3N/DMAP/R4NHCH2CO2Me and hydrolyzed withLiOH/EtOH/H2O to afford amide-acid 15a.

Preparation of Alkylated Pinacolol Sidechain (Scheme 3).

Ketone 7 is alkylated with LiHMDS/MeI and reduced with NaBH4/MeOH togive alcohol 16. Alcohol 16 is hydrolyzed with potassium hydroxide toafford alcohol-acid 17. Alcohol-acid 17 is reacted sequentially with 1)EDCI/Et3N/DMAP/R4NHCH2CO2Me; and 2) LiOH/EtOH/H2O to give amide-acid17a.

Preparation of Alkylsulfonylmethyl Sidechain Analogs (Scheme 4).

Benzylic bromide 11 is reacted with sodium alkylmercaptide and oxidizedwith mCPBA to give sulfone 18. Sulfone 18 is hydrogenolyzed with Pd—C/H2and alkylated with pinacolone chloride, potassium carbonate and sodiumiodide to produce ketone sulfone 19. Ketone sulfone 19 is reduced withsodium borohydride to afford alcohol sulfone 20.

Preparation of Unsymmetrical Central Link Diphenyl Scaffold (Scheme 5).

3-Substituted-4-hydroxybenzoic acid is coupled withEDCI/N-methyl-N-methoxyamine/DMAP and alkylated with benzyl bromide togive amide 21. Amide 21 is sequentially reacted with R2MgBr and R3MgBrGrignard reagents to afford tertiary alcohol 23. Alcohol 23 is reactedwith 2-substituted phenol 3 and BF3-OEt2 to produce diphenylalkane 24.Diphenylalkane 24 is reacted with triflic anhydride/pyridine andmethoxycarbonylated with Pd(OAc)₂, (DPPF or DPPB), carbon monoxide,MeOH, and Et3N to give ester 26. Ester 26 is hydrogenolyzed with Pd—C/H2and alkylated with pinacolone bromide to yield ketone ester 27. Ketoneester 27 is reduced with sodium borohydride and hydrolyzed withpotassium hydroxide to afford alcohol-acid 28. Alcohol-acid 28 iscoupled with EDCI/Et3N/DMAP/R4NHCH2CO2Me and hydrolyzed withLiOH/EtOH/H2O to afford amide-acid 28a.

Preparation of Tertiary Alcohol Sidechain Analog (Scheme 6).

Phenol 4 is alkylated with pinacolone bromide and reacted with MeMgBr orEtMgBr to give alcohol 29. Alcohol 29 is hydrogenolyzed with Pd—C/H2,reacted with triflic anhydride/pyridine and methoxycarbonylated toafford ester 30. Ester 30 is hydrolyzed with potassium hydroxide,coupled with EDCI/Et3N/DMAP/R4NHCH2CO2Me, and hydrolyzed to producetertiary alcohol amide-acid 31.

Preparation of Direct Linked Tetrazole (Scheme 7).

Acid 8 is reacted with formamide and sodium methoxide to give primaryamide 32. Primary amide 32 is treated with trifluoroacetic acid andmethylene chloride followed by 2-chloro-1,3-dimethyl-2-imidazoliniumhexafluorophosphate to give nitrile 33. Nitrile 33 is reacted withsodium azide and triethylammonium hydrochloride inN-methylpyrrolidin-2-one to afford tetrazole 34.

Preparation of Amide (Scheme 8).

Acid 8 is reacted with diphenyl phosphorus azide and triethylaminefollowed by treatment with dimethylamine and 4-(dimethylamino)pyridineto yield amide 35.

Preparation of Esters (Scheme 9).

Acid 8 is treated with sodium iodide and N,N-dimethyl-2-chloroacetamideto give ester 36. Acid 8 is treated with sodium iodide andN-morpholinocarbonylmethyl chloride to give ester 37.

Alternative Synthesis of Diphenylalkyl Scaffold (Scheme 10).

Phenol 2 is heated with pTSA to give olefin 38. Olefin 38 is alkylatedwith 2-chloropinacolone and reacted with a 2-substituted phenol/BF3-OEt2to yield phenol 40. Phenol 40 is converted to the corresponding phenolictriflate and reduced to alcohol 41. Alcohol 41 is methoxycarbonylated toafford ester 42. Ester 42 is hydrolyzed to produce acid 8.

Synthesis of Pentynol Phenyl alkyl Phenyl Acids (Scheme 11).

Ester 26 is hydrogenolyzed with Pd—C/H2 and reacted with Tf2O/pyridineto give triflate 43. Triflate 43 is sequentially reacted with 1)TMS-acetylene, PdCl2(PPh₃)₂, Et3N, and DMF and 2) CsF and water toafford acetylene 44. Acetylene 44 is treated with Zn(OTf)₂/t-butylaldehyde/chiral auxiliary (with or without) to give alcohol 46.Alternatively, acetylene 44 is reacted with LiHMDS/ketone 45 to givealcohol 46. Alcohol 46 is hydrolyzed with KOH/EtOH/H2O to afford acid47. Acid 47 is sequentially reacted with 1) EDCI/Et3N/DMAP/R4NHCH2CO2Meand 2) LiOH/EtOH/H₂O to give amide-acid 48.

Synthesis of Cis-Pentenol Phenyl Alkyl Phenyl Acids (Scheme 12).

Amide-acid 48 is hydrogenated with Lindlar catalyst to affordcis-pentenol amide-acid 49.

Synthesis of trans-Pentenol Phenyl Alkyl Phenyl Acids (Scheme 13).

Triflate 25 is sequentially reacted with 1) TMS-acetylene, PdCl2(PPh3)2,Et3N, and DMF and 2) CsF and water to afford acetylene 50. Acetylene 50is treated with Zn(OTf)2/t-butyl aldehyde/chiral auxiliary (with orwithout) to give alcohol 51. Alternatively, acetylene 50 is reacted withLiHMDS/ketone 45 to give alcohol 51. Alcohol 51 is reduced with LAH orDiBAH to afford trans-pentenol 52. Trans-pentenol 52 is sequentiallyreacted with 1) Pd—C/H2; 2) Tf2o/pyridine; 3) Pd(OAc)₂, DPPF, CO, MeOH,Et3N, DMF; 4) KOH/EtOH/H2O; 5) EDCI/Et3N/DMAP/R4NHCH2CO2Me; and 6)LiOH/EtOH/H2O to give trans-pentenol amide-acid 53. For reaction step 3,DPPB and DMSO.

EXAMPLES Abbreviations

The following examples use several standard abbreviations, for example;“RT” is room temperature, “Rt” or t_(ret) are symbols for retentiontime, and “Hex” refers to hexanes

Concentration is performed by evaporation from RT to about 70° C. undervacuum (1-10 mm)

Example 1 Preparation of racemic3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane

A. 3′,3′-Bis[4-hydroxy-3-methylphenyl]pentane

To a mixture of o-cresol (196 g, 1.81 mol) and 3-pentanone (60 ml, 0.57mol) is added methanesulfonic acid (45 ml, 0.69 mol) and stirred for 3days. The reaction is basified to pH 8 with satd Na₂CO₃ and extractedwith EtOAc. The organic layer is washed with water (6×500 ml), Na₂SO₄dried, concentrated, chromatographed (2 kg SiO2, Hex to 80% EtOAc/Hex),and triturated with Hex to give the title compound as a white solid (100g, 61%).

NMR 400 mHz (DMSO): δ 0.49 (t, J=7.3 Hz, 6H), 1.91 (q, J=7.3 Hz, 4H),2.02 (s, 6H), 6.61 (d, 3=8.3 Hz, 2H), 6.73 (d, J=8.3 Hz, 2H), 6.76 (s,2H), 8.94 (s, 2H).

High Res. EI-MS: 284.1794; calc. for C₁₉H₂₄O₂: 284.1776.

B.3′-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl)]-3′-[4-hydroxy-3-methylphenyl]pentane

To a mixture of 60% NaH disp (8.0 g, 200 mmol) and DMF (600 ml) is added3,3-bis[4-hydroxy-3-methylphenyl]pentane (56.88 g, 200 mmol) and stirredfor 2 h. To the reaction is added 3,3-dimethyl-1-bromo-2-butanone (26.93ml, 200 mmol) dropwise and stirred overnight. The solvent is removedin-vacuo. To the resulting residue is added EtOAc/water (800 ml/200 ml),acidified to pH 3 with 5N HCl, and partitioned. The organic layer iswashed with water (2×), brine, Na₂SO₄ dried, concentrated, andchromatographed (3 kg SiO₂, hex to 15% EtOAc/hex) to give the titlecompound as a white solid (35 g, 46%).

NMR (300 mHz, DMSO): δ 0.52 (t, J=7.3 Hz, 6H), 1.16 (s, 9H), 1.95 (q,J=7.3 Hz, 4H), 2.04 (s, 3H), 2.12 (s, 3H), 5.05 (s, 2H), 6.57 (d, J=9.1Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.81 (m, 2H), 8.97 (s, 1H).

ES-MS: 400 (M+NH4).

C.3′-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane

To a 0° C. solution of3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl)]-3′-[4-hydroxy-3-methylphenyl]pentane(20 g, 52 mmol), pyridine (30 ml) is added Tf₂O (9.7 ml, 57 mmol). Themixture is warmed to RT and stirred 14 h. The reaction is concentrated.The residue is partitioned between Et₂O/1N HCl. The organic layer iswashed with water, brine, Na₂SO₄ dried, concentrated, andchromatographed (hex to 10% EtOAc/hex) to give the title compound as anoil (26.3 g, 98%).

NMR (300 mHz, DMSO): δ 0.53 (t, J=7.3 Hz, 6H), 1.16 (s, 9H), 2.04 (q,J=7.3 Hz, 4H), 2.14 (s, 3H), 2.28 (s, 3H), 5.07 (s, 2H), 6.61 (d, J=8.8Hz, 1H), 6.86 (dd, J=2.2, 8.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 7.10 (dd,J=2.2, 8.8 Hz, 1H), 7.25 (m, 2H).

ES-MS: 532.5 (M+NH4).

D.3′-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane

To a 0° C. mixture of3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane(25.5 g, 49.5 mmol) and MeOH (200 ml) is added NaBH₄ (2.63 g, 59.4 mol)in portions. After stirring for 15 m, the reaction is allowed to warm toRT and stirred for 16 h. The reaction is concentrated and partitionedbetween Et₂O/1N HCl. The organic layer is washed with water, Na₂SO₄dried, and concentrated to give the title compound as an oil (26.0 g,quant).

NMR (300 mHz, DMSO): δ 0.55 (t, J=7.3 Hz, 6H), 0.92 (s, 9H), 2.04 (q,J=7.3 Hz, 4H), 2.11 (s, 3H), 2.28 (s, 3H), 3.46 (m, 1H), 3.76 (m, 1H),4.03 (m, 1H), 4.78 (d, J=5.5 Hz, 1H), 6.89 (m, 3H), 7.10 (dd, J=1.8, 8.8Hz, 1H), 7.23 (m, 2H).

High Res. EI-MS, m/e: 516.2171; calc. for C₂₆H₃₅F₃O₅S: 516.2157.

E.3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane

A mixture of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane(27 g, 52.2 mmol), Pd(OAc)₂ (1.2 g, 5.22 mmol), Dppf (5.8 g, 10.4 mmol),MeOH (21 ml, 522 mmol), Et₃N (22 ml, 157 mmol), and DMF (100 ml) ispressurized with carbon monoxide (1000 psi) and heated to 110° C. for 48h. After cooling, the reaction is filtered through diatomaceous earthwith EtOAc wash. The filtrate is diluted with 1:1 Et₂O:EtOAc, washedwith 1N HCl, and filtered through diatomaceous earth, Na₂SO₄ dried,concentrated, and chromatographed (hex to 10% EtOAc/hex) to give thetitle compound (14 g, 63%).

NMR 300 MHz (DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 0.92 (s, 9H), 2.04 (q,J=7.3 Hz, 4H), 2.09 (s, 3H), 2.46 (s, 3H), 3.45 (m, 1H), 3.76 (m, 4H),4.02 (m, 1H), 4.78 (d, J=5.5 Hz, 1H), 6.83 (m, 2H), 6.92 (dd, J=2.2, 8.4Hz, 1H), 7.07 (m, 2H), 7.74 (d, J=8.1 Hz, 1H).

High Res. FAB-MS: 426.2750; calc. for C₂₇H₃₈O₄: 426.2770.

Example 2 Preparation of racemic3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane

A mixture of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane(8.3 g, 19.4 mmol), EtOH (100 ml), water (100 ml) is added KOH (10.8 g,97 mmol) and heated to 75° C. for 8 h. The reaction is concentrated witha stream of nitrogen and the residue is partitioned between 1:1Et₂O:EtOAc and 1N HCl. The organic layer is washed with water, Na₂SO₄dried, concentrated, and chromatographed (gradient 20% EtOAc/MeCl₂ to30% EtOAc/CHCl₃) to give the title compound as a white foam (7.85 g,95%).

NMR mHz (DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 0.92 (s, 9H), 2.05 (q, J=7.3Hz, 4H), 2.10 (s, 3H), 2.47 (s, 3H), 3.45 (m, 1H), 3.76 (m, 1H), 4.02(dd, J=3.3, 9.9 Hz, 1H), 4.78 (d, J=5.1 Hz, 1H), 6.83 (m, 2H), 6.92 (dd,J=1.8, 8.4 Hz, 1H), 7.05 (m, 2H), 7.72 (d, J=8.1 Hz, 1H), 12.60 (br s,1H).

High Res. ES-MS: 435.2498; calc. for C₂₆H₃₆O₄+Na: 435.2511.

Example 3A and Example 3B Preparation of enantiomers of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl)]pentane

A mixture of racemic3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl)]pentane,Example 3, is chromatographed with a ChiralPak AD column to giveenantiomer 1, Example 3A (110 mg, 37%) and enantiomer 2, Example 3B (110mg, 37%).

Enantiomer 1, Example 3A

HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m(flow rate); Rt=6.2 m.

NMR eq. To Example 2.

High Res. ES-MS: 411.2521; calc. for C₂₆H₃₆O₄−H, 411.2535.

Enantiomer 2, Example 3B

HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m(flow rate); Rt=7.3 m.

NMR eq. To Example 2.

High Res. ES-MS: 413.2728; calc. for C₂₆H₃₆O₄+H, 413.2692.

Example 3A Alternate methodPreparation of enantiomer 1 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentanefrom enantiomer 1 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane.

Using a procedure analogous to Example 2, enantiomer 1 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane,Example 4A, gave the title compound as a glassy solid (1.3 g, quant).

Enantiomer 1, Example 3A

HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m(flow rate); Rt=7.0 m.

NMR eq. To Example 2.

High Res. ES-MS: 435.2533; calc. for C₂₆H₃₆O₄+Na: 435.2511.

High Res. ES-MS: 430.2943; calc. for C₂₆H₃₆O₄+NH₄: 430.2943.

HPLC correlation of Example 3A (derived from chiral HPLC of 2) and 3A(derived from the hydrolysis of 4A):

A mixture of Example 3A (1 mg) (derived from chiral HPLC of 2) and 3A (1mg)(derived from the hydrolysis of 4A) is dissolved in TFA/20% IPA/80%and analyzed by HPLC; ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80%heptane; 1 ml/m (flow rate); to give a single peak with Rt=7.0 m.

Example 3B alternate methodPreparation of enantiomer 2 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentanefrom enantiomer 2 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane.

Using a procedure analogous to Example 2, enantiomer 2 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane,Example 4B, gave the title compound as a glassy solid (1.3 g, quant).

Enantiomer 2, Example 3B

HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m(flow rate); Rt=8.0 m

NMR eq. To Example 2.

High Res. ES-MS: 435.2536; calc. for C₂₆H₃₆O₄+Na: 435.2511.

HPLC correlation of Example 3B (derived from chiral HPLC of 2) and 3B(derived from the hydrolysis of 4B):

A mixture of Example 3B (1 mg) (derived from chiral HPLC of 2) and 3B (1mg)(derived from the hydrolysis of 4B) is dissolved in TFA/20% IPA/80%and analyzed by HPLC; ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80%heptane; 1 ml/m (flow rate); to give a single peak with Rt=8.16 m.

Example 4A and 4B Preparation of enantiomers of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane

A mixture of racemic3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane,Example 1, is chromatographed with a ChiralPak AD column to giveenantiomer 1, Example 4A (1.72 g, 49%) and enantiomer 2, Example 4B(1.72 g, 49%).

Enantiomer 1, Example 4A

HPLC: ChiralPak AD (4.6×250 mm); 15% IPA/80% heptane; 1 ml/m (flowrate); Rt=5.4 m

NMR eq. To Example 1.

High Res. ES-MS: 444.3130; calc. for C₂₇H₃₈O₄+NH₄: 444.3114.

Enantiomer 2, Example 4B

HPLC: ChiralPak AD (4.6×250 mm); 15% IPA/80% heptane; 1 ml/m (flowrate); Rt=8.0 m.

NMR eq. To Example 1.

High Res. ES-MS: 444.3134; calc. for C₂₇H₃₈O₄+NH₄: 444.3114.

Example 5 Preparation of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methylsulfonylaminocarbonyl-3-methylphenyl)]pentane

To a mixture of methane sulfonamide (92 mg, 0.97 mmol), EDCI (186 mg,0.97 mmol), DMAP (118 mg, 0.97 mmol) and CH₂Cl₂ (7 ml) is added3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane,Example 1, (400 mg, 0.97 mmol) and stirred overnight. The reaction isdiluted with CH₂Cl₂, washed with 1N HCl (4×20 ml), Na₂SO₄ dried,concentrated, and chromatographed (gradient CHCl₃ to 10% CH₃CN/CHCl₃) togive the title compound as a solid (240 mg, 51%).

NMR mHz (DMSO): δ 0.60 (t, J=7.3 Hz, 6H), 1.01 (s, 9H), 2.06 (q, J=7.3Hz, 4H), 2.17 (s, 3H), 2.42 (d, J=2.9 Hz, 1H), 2.49 (s, 3H), 3.43 (s,3H), 3.70 (d, J=8.8 Hz, 1H), 3.86 (t, J=8.8 Hz, 1H), 4.09 (dd, J=2.4,9.3 Hz, 1H), 6.71 (d, 8.8 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.91 (dd,J=2.4, 8.8 Hz, 1H), 7.09 (m, 2H), 7.37 (d, J=7.8 Hz, 1H), 12.30 (s, 1H).

High Res. ES-MS: 490.2633; calc. for C₂₇H₃₉NO₅S+H, 490.2627.

Example 6 Preparation of3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-carboxylethyl)-3-methylphenyl]pentane

A. 3′-[4-Benzyloxy-3-methylphenyl]-3′-[4-hydroxy-3-methylphenyl]pentane

To a solution of 3,3-bis[4-hydroxy-3-methylphenyl]pentane (10 g, 35.2mmol) and DMF (180 ml) is added 60% NaH disp (1.4 g, 35.2 mmol). Afterstirring for 30 m, to the reaction is added benzyl bromide (4.2 ml, 35.2mmol). The mixture is stirred for 14 h and concentrated in vacuo. Theresidue is partitioned between Et₂O/water. The organic layer is washedwith 1N HCl, water, brine, Na₂SO₄ dried, concentrated, andchromatographed (MeCl₂) to give the title compound as an oil (6.5 g,49%).

NMR 300 MHz (DMSO): δ 0.52 (t, J=7.3 Hz, 6H), 1.96 (q, J=7.3 Hz, 4H),2.04 (s, 3H), 2.12 (s, 3H), 5.05 (s, 2H), 6.63 (d, J=8.1 Hz, 1H), 6.75(dd, J=2.2, 8.1 Hz, 1H), 6.79 (s, 1H), 6.89 (m, 3H), 7.44 (m, 5H), 8.96(s, 1H).

High Res. FAB-MS: 374.2237; calc. for C₂₆H₃₀O₂: 374.2246.

B.3′-[4-Benzyloxy-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane

Using a procedure analogous to Example 1C,3′-[4-benzyloxy-3-methylphenyl]-3′-[4-hydroxy-3-methylphenyl]pentanegives the title compound as an oil (21.5 g, 91%).

NMR 300 MHz (DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 2.05 (q, J=7.3 Hz, 4H),2.14 (s, 3H), 2.28 (s, 3H), 5.06 (s, 2H), 7.10 (dd, J=2.2, 8.8 Hz, 1H),7.26 (m, 2H), 7.34 (d, J=7.0 Hz, 1H), 7.39 (m, 4H).

High Res. FAB-MS: 506.1743; calc. for C₂₇H₂₉F₃O₄S: 506.1739.

C.3′-[4-Benzyloxy-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane

To a mixture of3′-[4-benzyloxy-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane(5.3 g, 10.5 mmol) and THF (5 ml) is sequentially added Pd(dppf)Cl₂ (860mg, 1.05 mmol), LiCl (1.78 g, 42 mmol), and 0.5 M BrZnCH₂CH₂CO₂Et in THF(63 ml, 31.4 mmol). The mixture is heated to 60° C. for 18 h. Aftercooling to RT, the mixture is concentrated in-vacuo, partitioned betweenEt₂O/EtOAc/1N HCl. The organic layer is washed with 1N HCl, water,Na₂SO₄ dried, concentrated, and chromatographed (hex to 10% EtOAc/hex)to give the title compound (2.5 g, 52%).

NMR 400 MHz (DMSO): δ 0.51 (t, J=7.3 Hz, 6H), 1.14 (t, J=7.1 Hz, 3H),2.00 (q, J=7.3 Hz, 4H), 2.10 (s, 3H), 2.18 (s, 3H), 2.52 (t, J=8.1 Hz,2H), 2.75 (t, J=8.1 Hz, 2H), 4.01 (q, J=7.1 Hz, 2H), 5.03 (s, 2H), 6.87(m, 5H), 6.98 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.3 Hz, 1H), 7.37 (m, 2H),7.43 (d, J=7.1 Hz, 2H).

High Res. ES-MS: 476.3178; calc. for C₃₁H₃₈O₃+NH₄: 476.3165.

D.3′-[4-Hydroxy-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane

A mixture of 3′-[4-benzyloxy-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane (2.4 g, 5.45 mmol), EtOH (20 ml), and 10%Pd/C (250 mg) is hydrogenated at atmospheric pressure for 18 h. Thereaction is filtered through diatomaceous earth with EtOAc wash. Thefiltrate is concentrated to give the title compound (2 g, quant).

NMR 400 MHz (DMSO): δ 0.49 (t, J=7.3 Hz, 6H), 1.12 (t, J=7.1 Hz, 3H),1.95 (q, J=7.3 Hz, 4H), 2.01 (s, 3H), 2.18 (s, 3H), 2.52 (t, J=7.7 Hz,2H), 2.75 (t, J=7.7 Hz, 2H), 4.01 (q, J=7.1 Hz, 2H), 6.61 (d, J=8.3 Hz,1H), 6.73 (d, J=8.3 Hz, 1H), 6.77 (s, 1H), 6.86 (m, 2H), 6.97 (d, J=7.8Hz, 1H), 8.98 (s, 1H).

High Res. ES-MS: 391.2218; calc. for C₂₄H₃₂O₃+Na: 391.2249.

E.3′-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 1B,3′-[4-hydroxy-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentaneand 1-bromo-3,3-dimethyl-2-butanone gave the title compound (2.1 g,83%).

¹H NMR 400 MHz (DMSO-d₆): δ 0.50 (t, J=7.3 Hz, 6H), 1.05-1.14 (m, 12H),1.98 (q, J=7.3 Hz, 4H), 2.10 (s, 3H), 2.18 (s, 3H), 2.52 (t, J=7.7, 2H),2.75 (t, J=7.7, 2H), 4.02 (q, J=7.2 Hz, 2H), 5.04 (s, 2H), 6.55 (d,J=8.3 Hz, 1H), 6.82-6.89 (m, 4H), 6.98 (d, J=8.1, 1H).

High Res. ES-MS: 489.2990; calc. for C₃₀H₄₂O₄+Na: 489.2981.

F.3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxylethyl-3-methylphenyl]pentane

Using a procedure analogous to Example 2,3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentanegives the title compound (1.8 g, 95%).

¹H NMR 300 MHz (DMSO-d₆): δ 0.52 (t, J=7.3 Hz, 6H), 1.16 (s, 9H), 2.01(q, J=7.32 Hz, 4H), 2.13 (s, 3H), 2.20 (s, 3H), 2.46 (t, J=7.3 Hz, 2H),2.74 (t, J=7.3 Hz, 2H), 5.06 (s, 2H), 6.58 (d, J=8.4 Hz, 1H), 6.89 (m,4H), 7.01 (d, J=7.7 Hz, 1H).

High Res. ES-MS: 461.2669; calc. for C₂₈H₃₈O₄+Na: 461.2668.

Example 7 Preparation of3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-dimethylcarbamoylethyl)-3-methylphenyl]pentane

To a 0° C. mixture of3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-carboxylethyl)-3-methylphenyl]pentane(500 mg, 1.14 mmol), pyridine (101 ul, 1.25 mmol), DMF (4.4 ul, 0.057mmol) and MeCl₂ (4 ml) is added oxalyl chloride (104 ul, 1.2 mmol).After stirring for 10 m, to the mixture is added 2M Me₂NH/THF (2.3 ml,4.56 mmol). To the reaction is added MeCl₂ (4 ml) and stirred at RT for2 h. The mixture is concentrated and partitioned between Et₂O/1N HCl.The organic layer is washed with water, Na₂SO₄ dried, concentrated, andchromatographed (hex to CH2Cl2 to 15% EtOAc/MeCl₂) to give the titlecompound as a solid (85 mg, 16%).

¹H NMR 400 MHz (DMSO-d₆): δ 0.51 (t, J=7.3 Hz, 6H), 1.14 (s, 9H), 1.96(q, J=7.3 Hz, 4H), 2.11 (s, 3H), 2.19 (s, 3H), 2.48 (t, J=7.2, J=8.8 Hz,2H, under DMSO peak), 2.69 (t, J=7.2, J=8.8 Hz, 2H), 2.79 (s, 3H), 2.88(s, 3H), 5.05 (s, 2H), 6.55 (d, J=8.8 Hz, 1H), 6.84-6.87 (m, 4H), 6.99(d, J=8.3 Hz, 1H).

ES-MS: 466.2 (M+H).

Example 8 Preparation of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-dimethylcarbamoylethyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 1D,3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-dimethylcarbamoylethyl)-3-methylphenyl]pentanegives the title compound as a white glassy solid (65 mg, quant).

¹H NMR 300 MHz (DMSO-d₆): δ 0.53 (t, J=7.0 Hz, 6H), 0.92 (s, 9H), 6.96(q, J=6.96 Hz, 4H), 2.10 (s, 3H), 2.20 (s, 3H), 2.50 (t, J=6.9, J=8.4Hz, 2H, under DMSO peak), 2.71 (t, J=6.9, J=8.4 Hz, 2H), 2.80 (s, 3H),2.90 (s, 3H), 3.45 (m, 1H), 3.75 (m, 1H), 4.01 (dd, J=2.9, J=6.9 Hz,1H), 6.80 (d, J=8.4, 1H), 6.89 (m, 4H), 7.01 (d, J=8.0 Hz, 1H).

High Res. ES-MS: 490.3301; calc. for C₃₀H₄₅NO₃+Na: 490.3297.

Example 9 Preparation of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-dimethylcarbamoyl-t-ethylidene)-3-methylphenyl]pentane

To a mixture of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-trifluoromethylsulfonyloxy-3-methylphenyl]pentane(640 mg, 1.24 mmol), Pd(OAc)₂ (14 mg, 0.062), DPPP (51 mg, 0.124 mmol),and DMF (2.5 ml) is added Et₃N (0.69 ml, 4.96 mmol). The mixture ispurged with N₂ and N,N-dimethylacrylamide (0.39 ml, 3.71 mmol) is added.The reaction is heated to 80° C. for 14 h and then cooled. The mixtureis partitioned between EtOAc/water. The organic layer is washed with 1NHCl, water, brine, Na₂SO₄ dried, concentrated, and chromatographed(MeCl₂ to 60% EtOAc/MeCl₂) to give the title compound as a white foam(90 mg, 16%).

¹H NMR 300 MHz (DMSO-d₆): δ 0.55 (t, J=7.0 Hz, 6H), 0.92 (s, 9H), 2.04(q, J=7.0 Hz, 4H), 2.10 (s, 3H), 2.31 (s, 3H), 2.92 (s, 3H), 3.13 (s,3H), 3.45 (m, 1H), 3.75 (dd, J=7.4, 9.9 Hz, 1H), 4.02 (dd, J=3.3, 9.9Hz, 1H), 4.78 (d, J=5.1 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.87 (s, 1H),6.96 (m, 3H), 7.01 (s, 1H), 7.62 (m, 2H).

High Res. ES-MS: 466.3328; calc. for C₃₀H₄₄NO₃+H, 466.3321.

Preparation of enantiomers of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane

A.3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane

Using a procedure analogous to Example 1B,3′-[4-hydroxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentanegave the title compound as a white solid (19.5 g, 88%).

NMR 300 mHz (DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 1.16 (s, 9H), 2.05 (q,J=7.3 Hz, 4H), 2.13 (s, 3H), 2.47 (s, 3H), 3.79 (s, 3H), 5.07 (s, 2H),6.59 (d, J=9.1 Hz, 1H), 6.86 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 7.11 (s,1H), 7.72 (d, J=8.1 Hz, 1H).

High Res. ES-MS: 442.2953; calc. for C₂₇H₃₆O₄+NH₄: 442.2957.

B.3′-[4-(2-oxo-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane

To a −78° C. mixture of3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(2-methoxycarbonyl-3-methylphenyl)]pentane(2.0 g, 4.7 mmol) in THF (10 ml) is added 1M LiHMDS/THF (5.2 ml, 5.2mmol). The reaction is warmed to 45° C., stirred for 1.25 h, added MeI(351 ul, 5.6 mmol). After warming to RT and stirred overnight, thereaction is diluted with Et2O, washed with 1N HCl, water, and Na2SO4dried. The organic solution is concentrated and chromatographed (50%CHCl₃/hex) to give the title compound (1.75 g, 85%).

NMR 300 mHz (DMSO): δ 0.53 (t, J=7.3 Hz, 6H), 1.10 (s, 9H), 1.34 (d,J=6.6 Hz, 3H), 2.04 (q, J=7.3 Hz, 4H), 2.10 (s, 3H), 2.46 (s, 3H), 3.79(s, 3H), 5.32 (q, J=6.6 Hz, 1H), 6.88 (m, 3H), 7.05 (d, J=8.4 Hz, 1H),7.10 (s, 1H), 7.71 (d, J=8.1 Hz, 1H).

High Res. ES-MS: 456.3107; calc. for C₂₈H₃₈O₄+NH₄: 456.3114.

C.3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane

Using a procedure analogous to Example 1D,3′-[4-(2-oxo-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentanegives the title compound (1.6 g, 100%).

NMR 300 mHz (DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 1.19 (d,J=5.9 Hz, 3H), 2.07 (m, 7H), 2.48 (s, 3H), 3.08 (dd, J=1.1, 7.7 Hz, 1H),3.79 (s, 3H), 4.35 (d, J=7.7 Hz, 1H), 4.57 (br q, J=5.9 Hz, 1H), 6.84(m, 3H), 7.06 (br d, J=8.4 Hz, 1H), 7.14 (s, 1H), 7.72 (d, J=8.4 Hz,1H).

High Res. ES-MS: 456.3107; calc. for C₂₈H₃₈O₄+NH₄: 456.3114.

D. Enantiomers of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane

Using a procedure analogous to Example 1D,3′-[4-(2-oxo-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentanegave a racemic mixture of the title compound. The mixture ischromatographed (Chiralpak AD) to give enantiomer 1 (543 mg, 36%, Rt=)and enantiomer 2 (822 mg, 55%, Rt=).

Enantiomer 1 Example 10Da

NMR 300 mHz (DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 1.20 (d,J=6.2 Hz, 3H), 2.07 (m, 7H), 2.48 (s, 3H), 3.08 (dd, J=1.5, 7.7 Hz, 1H),3.79 (s, 3H), 4.35 (d, J=7.7 Hz, 1H), 4.57 (m, 1H), 6.84 (m, 3H), 7.06(dd, J=1.1, 8.4 Hz, 1H), 7.14 (s, 1H), 7.72 (d, J=8.4 Hz, 1H).

High Res. ES-MS: 458.3257; calc. for C₂₈H₄₀O₄+NH₄: 458.3270.

Enantiomer 2 Example 10Db

NMR 300 mHz (DMSO): eq. to enantiomer 1.

MS: 440.29 (M+).

High Res. ES-MS: calc. for C₂₇H₃₉NO₅S+H.

Example 11 Preparation of enantiomer 1 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane

Using a procedure analogous to Example 2, enantiomer 1 of3′-[4-(1-methyl-2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane,Example 10Da, gave the title compound (420 mg, 96%).

HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m(flow rate); Rt=m.

NMR 300 mHz (DMSO): δ 0.54 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), d, J=5.9 Hz,3H), 2.07 (m, 7H), 2.48 (s, 3H), 3.08 (dd, J=1.1, 7.7 Hz, 1H), 4.35 (d,J=7.7 Hz, 1H), 4.57 (m, 1H), 6.84 (m, 3H), 7.04 (d, J=8.1 Hz, 1H), 7.10(s, 1H), 7.72 (d, J=8.1 Hz, 1H), 12.60 (br s, 1H).

High Res. ES-MS: 875.5439; calc. for [C₂₇H₃₈O₄+Na]+C₂₇H₃₈O₄: 875.5438.

Example 12 Preparation of enantiomer 2 of3′-[4-(2-hydroxy-3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl)]pentane

Using a procedure analogous to Example 2, enantiomer 2 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane,Example 10Db, gave the title compound (680 mg, 94%).

HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA/20% IPA/80% heptane; 1 ml/m(flow rate); Rt=m.

NMR 300 mHz (DMSO): eq. to enantiomer 1.

High Res. ES-MS: 449.2657; calc. for C₂₇H₃₈O₄+Na: 449.2668.

Example 12a Preparation enantiomer 1 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 5, enantiomer 1 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane,Example 3A, and 5-aminotetrazole give the title compound (440 mg, 95%).

NMR 300 mHz (DMSO): 0.57 (t, J=7.3 Hz, 6H), 0.92 (s, 9H), 2.09 (m, 7H),2.40 (s, 3H), 3.46 (m, 1H), 3.76 (dd, J=7.3, 10.2 Hz, 1H), 4.03 (dd,J=3.3, 10.2 Hz, 1H), 4.79 (d, J=5.5 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H),6.89 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.12 (s,1H), 7.52 (d, J=8.1 Hz, 1H), 12.23 (s, 1H), 16.00 (br s, 1H).

High Res. ES-MS: 480.2983; calc. for C₂₇H₃₇N₅O₃+H, 480.2975.

Example 12b Preparation enantiomer 2 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 5, enantiomer 2 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane,Example 3B, and 5-aminotetrazole gives the title compound (385 mg, 83%).

NMR 300 mHz (DMSO): eq. to enantiomer of 1.

High Res. ES-MS: 480.2968; calc. for C₂₇H₃₇N₅O₃+H, 480.2975.

Example 13 Preparation of1-[4-(1-ethyl-1-{4-[(2-methanesulfonyl-ethylamino)-methyl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxy]-3,3-dimethyl-butan-2-one

A. Methyl4-(1-{4-[2-(tert-Butyldimethylsilanyloxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methyl-benzoate

To a solution of the methyl4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoate(4.79 g, 11.24 mmol), Example 1, in DMF (40 mL) is added imidazole (1.14g, 16.87 mmol) followed by the addition of TBSCl (1.78 g, 11.80 mmol).The mixture is stirred at RT overnight and concentrated. The mixture ispartitioned between 0.1 M HCl (100 mL) and EtOAc (100 mL). The aqueouslayer is extracted with EtOAC. The combined organic layers is MgSO₄dried, concentrated, and chromatographed (10% EtOAc/Hex) to give thetitle compound (4.37 g, 72%).

¹H NMR (CDCl₃): δ 0.04 (s, 3H), 0.10 (s, 3H), 0.60 (t, J=7.0 Hz, 6H),0.89 (s, 9H), 0.96 (s, 9H), 2.04-2.09 (m, 4H), 2.16 (s, 3H), 2.55 (s,3H), 3.66 (dd, J=5.6, 3.6 Hz, 1H), 3.82-3.86 (m, 4H), 3.97 (dd, J=10.0,3.2 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.83-7.06 (m, 4H), 7.79 (d, J=7.6Hz, 1H). ES-MS (m/z): calcd for C₃₃H₅₂O₄Si (M⁺): 540.9; found: 541.2.

B.[4-(1-{4-[2-(tert-Butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylphenyl]-methanol

To a 0° C. solution of the methyl4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methyl-benzoate(4.37 g, 8.09 mmol) in THF (50 mL) is added LiAlH₄ (0.31 g, 8.09 mmol).The reaction is stirred for 10 m and allowed to warm to RT overnight.The mixture is cooled to 0° C. and quenched successively with H₂O (0.3mL), 15% NaOH (0.3 mL) and H₂O (0.9 mL). The mixture is stirred for 10m, warmed to RT, stirred for 20 m, filtered through celite with EtOAc(100 mL) wash, and concentrated to give the title compound (4.14 g, 8.08mmol, 99%).

¹H NMR (CDCl₃): δ 0.04 (s, 3H), 0.10 (s, 3H), 0.59 (t, J=7.1 Hz, 6H),0.89 (s, 9H), 0.94 (s, 9H), 2.05 (q, J=7.1 Hz, 4H), 2.17 (s, 3H), 2.31(s, 3H), 3.66 (dd, J=6.0, 3.6 Hz, 1H), 3.70 (t, J=5.6 Hz, 1H), 3.84 (dd,J=9.8, 5.2 Hz, 1H), 3.97 (dd, J=9.8, 3.6 Hz, 1H), 4.67 (s, 2H), 6.65 (d,J=8.4 Hz, 1H), 6.88-7.02 (m, 4H), 7.21 (d, J=8.0 Hz, 1H). ES-MS (m/z):calcd for C₃₂H₅₆NO₃Si (M+NH₄)⁺: 530.9; found: 530.2.

C.4-(1-{4-[2-(t-Butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzaldehyde

To a solution of[4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylphenyl]methanol(0.25 g, 0.48 mmol) in CH₂Cl₂ (4 mL) is added powdered 4 Å molecularsieves (250 mg) followed by the addition of NMO (84 mg, 0.72 mmol), andTPAP (8.4 mg, 0.02 mmol). The resulting mixture is stirred at RT for 5m, filtered through silica gel, washed with EtOAc, and the combinedfiltrate is concentrated to give the title compound (0.20 g, 83%).

¹H NMR (CDCl₃): δ 0.04 (s, 3H), 0.10 (s, 3H), 0.61 (t, J=7.2 Hz, 6H),0.89 (s, 9H), 0.96 (s, 9H), 2.09 (q, J=7.2 Hz, 4H), 2.17 (s, 3H), 2.62(s, 3H), 3.67 (dd, J=5.4, 3.4 Hz, 1H), 3.85 (dd, J=9.8, 5.4 Hz, 1H),3.97 (dd, J=9.8, 3.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.84-6.92 (m, 2H),7.08 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 10.21 (s,1H). ES-MS (m/z): calcd for C₃₂H₅₁O₃Si (M+H)⁺: 511.8; found: 511.2.

D.[4-(1-{4-[2-(t-Butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzyl]-(2-methanesulfonylethyl)amine

To a mixture of4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzaldehyde(2.40 g, 4.71 mmol), Et₃N (0.9 ml, 6.12 mmol), and2-aminoethylmethylsulfone hydrochloride (0.78 g, 5.18 mmol) is treatedwith Ti(OiPr)₄ (1.8 ml, 6.12 mmol). The mixture is stirred for 1 h,diluted with CH₃OH (20 mL), then NaBCNH₃ (0.33 g, 5.18 mmol) is added.The mixture is stirred overnight, quenched with H₂O (3 mL), stirred for1 h., and filtered through SiO₂ with EtOAc (100 mL) wash. The filtrateis concentrated and chromatographed (75-80% EtOAc) to give the titlecompound (1.47 g, 2.38 mmol, 51%).

¹H NMR (CDCl₃), δ 0.05 (s, 3H), 0.12 (s, 3H), 0.61 (t, J=7.4 Hz, 6H),0.91 (s, 9H), 0.97 (s, 9H), 2.05 (q, J=7.4 Hz, 4H), 2.19 (s, 3H), 2.33(s, 3H), 2.99 (s, 3H), 3.21-3.27 (m, 3.5H), 3.66-3.72 (m, 1.5H), 3.83(s, 2H), 3.86 (t, J=5.9 Hz, 1H), 3.98 (dd, J=9.8, 3.4 Hz, 1H), 6.65 (d,J=8.3 Hz, 1H), 6.86-6.88 (m, 1H), 6.92 (dd, J=8.3, 2.4 Hz, 1H), 6.99 (s,1H), 7.00 (bs, 1H), 7.14 (d, J=8.2 Hz, 1H). ES-MS (m/z): calcd forC₃₅H₆₀O₄SSi (M+H)⁺: 619.0; found: 619.6.

E.1-[4-(1-Ethyl-1-{4-[(2-methanesulfonylethylamino)methyl]-3-methylphenyl}propyl)-2-methylphenoxy]-3,3-dimethylbutan-2-ol

To a mixture of[4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzyl]-(2-methanesulfonylethyl)amine(1.47 g, 2.43 mmol) in THF (30 mL) is added 1M TBAF (2.7 mL, 2.7 mmol),and refluxed for 2 h. After cooling to RT, the mixture is diluted withH₂O (20 mL) and extracted with EtOAc (3×30 mL). The combined organiclayers are MgSO₄ dried, concentrated, and chromatographed (80%EtOAc/Hex) to give the title compound (0.97 g, 1.93 mmol, 79%).

¹H NMR (CDCl₃), δ 0.60 (t, J=7.4 Hz, 6H), 1.02 (s, 9H), 2.05 (q, J=7.4Hz, 4H), 2.18 (s, 3H), 2.34 (s, 3H), 3.01 (s, 3H), 3.32 (bs, 4H), 3.71(dd, J=8.8, 2.4 Hz, 1H), 3.86 (t, J=9.3 Hz, 1H), 3.88 (s, 2H), 4.09 (dd,J=9.3, 2.4 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.89 (bs, 1H), 6.90-6.96 (m,1H), 6.98 (s, 1H), 7.00 (s, 1H), 7.13 (d, J=7.5 Hz, 1H). ES-MS (m/z):calcd for C₂₉H₄₆O₄S (M+H)⁺: 504.8; found: 504.4.

F. t-Butyl(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzyl)-(2-methanesulfonylethyl)carbamate

To a mixture of1-[4-(1-ethyl-1-{4-[(2-methanesulfonylethyl-amino)methyl]-3-methylphenyl}propyl)-2-methylphenoxy]-3,3-dimethylbutan-2-ol(0.97 g, 1.92 mmol), NaHCO₃ (0.32 g, 3.84 mmol), H₂O (10 mL), and THF (5mL), is added (Boc)₂O (0.46 g, 2.11 mmol). The reaction is stirredovernight, diluted with H₂O (10 mL), and extracted with EtOAc (2×20 mL).The combined organic layers are washed with 0.1 M HCl (15 mL), brine (10mL); MgSO₄ dried, and chromatographed (40% EtOAc/Hex) to give the titlecompound (0.86 g, 1.43 mmol, 74%).

¹H NMR (CDCl₃), δ 0.61 (t, J=7.3 Hz, 6H), 1.02 (s, 9H), 1.45 (bs, 9H),2.05 (q, J=7.3 Hz, 4H), 2.19 (s, 3H), 2.24 (s, 3H), 2.44 (bs, 1H),2.70-3.20 (b, 5H), 3.58 (bs, 2H), 3.71 (dd, J=8.8, 2.9 Hz, 1H), 3.86 (t,J=8.8 Hz, 1H), 4.10 (dd, J=8.8, 2.9 Hz, 1H), 4.47 (s, 2H), 6.71 (d,J=8.4 Hz, 1H), 6.80-7.01 (m, 5H). ES-MS (m/z): calcd for C₃₄H₅₇N₂O₆S(M+NH₄)⁺: 621.9; found: 621.3.

G. t-Butyl(4-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzyl)-(2-methanesulfonylethyl)carbamate

Using a procedure analogous to Example 13C, from t-butyl(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzyl)-(2-methanesulfonylethyl)carbamate(0.26 g, 0.43 mmol) to give the title compound (0.25 g, 0.42 mmol, 95%).

¹H NMR (CDCl₃), δ 0.60 (t, J=7.5 Hz, 6H), 1.26 (s, 9H), 1.48 (bs, 9H),2.05 (q, J=7.5 Hz, 4H), 2.23 (s, 3H), 2.25 (s, 3H), 2.60-3.20 (m, 5H),3.57 (bs, 2H), 4.46 (s, 2H), 4.84 (s, 2H), 6.50 (d, J=8.1 Hz, 1H),6.80-7.01 (m, 5H). ES-MS (m/z): calcd for C₃₄H₅₁O₆S: 601.9; found:602.2.

H.1-[4-(1-Ethyl-1-{4-[(2-methanesulfonylethylamino)-methyl]-3-methylphenyl}propyl)-2-methylphenoxy]-3,3-dimethylbutan-2-one

To a mixture of t-butyl(4-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzyl)-(2-methanesulfonylethyl)carbamate(0.25, g, 0.41 mmol) and CH₂Cl₂ (5 mL) is added TFA (5 mL,), stirred for10 m, and concentrated. The residue is diluted with EtOAc (100 mL),washed with sat.d NaHCO₃ (2×30 mL); MgSO₄ dried, and chromatographed(90% EtOAc) to give the title compound (0.19 g, 0.39 mmol, 95%).

¹H NMR (CDCl₃), δ 0.61 (t, J=7.2 Hz, 6H), 1.27 (s, 9H), 2.05 (q, J=7.2Hz, 4H), 2.25 (s, 3H), 2.32 (s, 3H), 2.99 (s, 3H), 3.25 (s, 4H), 3.81(s, 2H), 4.84 (s, 2H), 6.49 (d, J=8.3 Hz, 1H), 6.85-7.00 (m, 4H), 7.13(d, J=7.7 Hz, 1H). ES-MS (m/z): calcd for C₂₉H₄₄NO₄S (M+H)⁺: 502.7;found: 502.2.

Example 14 Preparation of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide

To a mixture of4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoicacid, Example 1, (0.53 g, 1.29 mmol), 2-aminoethylmethylsulfonehydrochloride (0.21 g, 1.29 mmol), HOBt (0.19 g, 1.43 mmol), Et₃N (0.72mL, 5.19 mmol) and CH₂Cl₂ (10 mL) is added EDCI (0.249 g, 1.29 mmol) andstirred overnight. The reaction is diluted with CH₂Cl₂ (50 mL), washedwith 1M HCl (2×30 mL), H₂O (20 mL), satd NaHCO₃ (2×20 mL), and brine (20mL). The organic layer is MgSO₄ dried, concentrated, and chromatographed(75% EtOAc/Hex) to give the title compound (0.51 g, 76%).

¹H NMR (CDCl₃), δ 0.59 (t, J=7.8 Hz, 6H), 1.01 (s, 9H), 2.00-2.28 (m,4H), 2.17 (s, 3H), 2.41 (s, 3H), 3.00 (s, 3H), 3.35 (t, J=5.6 Hz, 1H),3.70 (bd, J=8.6 Hz, 1H), 3.85 (t, J=9.1 Hz, 1H), 3.97 (dd, J=12.3, 5.6Hz, 2H), 4.09 (dd, J=9.1, 3.0 Hz, 1H), 6.53 (t, J=5.9 Hz, 1H), 6.69 (d,J=7.8 Hz, 1H), 6.85 (s, 1H), 6.91-7.01 (m, 2H), 7.25-7.29 (m, 2H). ES-MS(m/z): calcd for C₂₉H₄₄NO₅S (M+H)⁺: 518.7; found: 518.3.

Example 15A & 15B Preparation of enantiomer 1 and 2 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide

A racemic mixture of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide(0.34 g), Example 14, is chromatographed (HPLC: ChiralPak AD, 60%EtOH/Hept) to give enantiomer 1 (0.10 g, 29%, rt=4.9 m) and enantiomer 2(0.125 g, 37%, rt=6.3 m).

Example 15A, 2071445 (enantiomer 1):

HPLC: ChiralPak AD (4.6×250 mm); 60% EtOH/Hept; 1.0 mL/m (flow rate);rt=4.9 m; @ 240 nm.

NMR & LC/MS: equivalent to the racemate, Example 14.

Example 15B, 2071447 (enantiomer 2):

HPLC: ChiralPak AD (4.6×250 mm); 60% EtOH/Hept; 1.0 mL/m (flow rate); rt6.3 m; @ 240 nm.

NMR & LC/MS: equivalent to the racemate, Example 14.

Example 16 Preparation of4-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide

Using a procedure analogous to Example 13C, from4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide,Example 14, (0.08 g, 0.16 mmol), NMO (27 mg, 0.24 mmol), and TPAP (2.8mg, 0.08 mmol) are reacted for 1 h to give the title compound (0.06 g,76%).

¹H NMR (CDCl₃): δ 0.60 (t, J=7.4 Hz, 6H), 1.27 (s, 9H), 2.05 (q, J=7.4Hz, 4H), 2.24 (s, 3H), 2.42 (s, 3H), 3.01 (s, 3H), 3.36 (t, J=6.0 Hz,2H), 3.94-4.02, (m, 2H), 4.82 (s, 2H), 6.46-6.57 (m, 2H), 6.82-7.23 (m,5H). ES-MS (m/z): calcd for C₂₉H₄₂NO₅S (M+H)⁺: 516.7; found: 516.4.

Example 17 Preparation of4-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzoicacid

To a mixture of4-{1-[4-(3,3-dimethyl-2-hydroxybutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzoicacid, Example 1, (0.50 g, 1.22 mmol) in CH₂Cl₂ (10 mL) is added asolution of the Dess-Martin reagent (0.57 g, 1.34 mmol) in CH₂CL₂ (10mL) dropwise and stirred for 2 h. The reaction is diluted with EtOAc(100 mL), washed with 10% Na₂SO₃ (2×20 ml), 0.1 M HCl (20 ml), and H₂O(20 ml). The organic layer is MgSO₄ dried, and concentrated to give thetitle compound (0.48 g, 1.17 mmol, 95%).

¹H NMR (CDCl₃), δ 0.62 (t, J=7.2 Hz, 6H), 1.27 (s, 9H), 2.09 (q, J=7.2Hz, 4H), 2.25 (s, 3H), 2.61 (s, 3H), 4.85 (s, 2H), 6.51 (d, J=8.8 Hz,1H), 6.85-6.91 (m, 2H), 7.05-7.10 (m, 2H), 7.93 (d, J=9.0 Hz, 1H). ES-MS(m/z): calcd for C₂₆H₃₈NO₄ (M+NH₄)⁺: 428.6; found: 428.3.

Example 18 Preparation of enantiomer 1 of[(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid

A. Enantiomer 1 of[(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid methyl ester

Using a procedure analogous to Example 5, from enantiomer 1 of4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoicacid, Example 3A, (1.28 g, 3.17 mmol) and N-methyl glycine methyl esterhydrochloride (0.48 g, 3.41 mmol) to give the title compound (1.43 g,2.88 mmol, 93%). ¹H NMR (CDCl₃), δ 0.57-0.65 (m, 6H), 1.02 (s, 9H),2.00-2.11 (m, 4H), 2.18 (s, 3H), 2.25 (s, 0.80H), 2.32 (s, 2.20H), 2.89(s, 2.20H), 3.15 (s, 0.80H), 3.70 (s, 0.8H), 3.72 (d, J=2.6 Hz, 1H),3.79 (s, 2.2H), 3.86 (t, J=8.8 Hz, 1H), 3.91 (s, 0.52H), 4.09 (dd,J=7.0, 2.6 Hz, 1H), 4.32 (bs, 1.48H), 6.70 (d, J=8.3 Hz, 1H), 6.85-7.11(m, 5H). ES-MS (m/z): calcd for C₃₀H₄₄NO₅ (M+H)⁺: 498.7; found: 498.3.

B. Enantiomer 1 of[(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid

Using a procedure analogous to Example 2, from enantiomer 1 of[(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid methyl ester (1.43 g, 2.88 mmol) to give the title compound (1.24g, 2.57 mmol, 90%). ¹H NMR (CDCl₃), δ 0.56-0.63 (m, 6H), 1.02 (s, 9H),2.01-2.09 (m, 4H), 2.11 (s, 0.7H), 2.18 (s, 2.3H), 2.23 (s, 0.70H), 2.29(s, 2.30H), 2.91 (s, 2.30H), 3.14 (s, 0.70H), 3.71 (dd, J=8.8, 2.6 Hz,1H), 3.86 (t, J=8.8 Hz, 1H), 3.92 (s, 0.47H), 4.09 (dd, J=8.8, 2.6 Hz,1H), 4.33 (bs, 1.53H), 6.69 (d, J=8.8 Hz, 0.23H), 6.70 (d, J=8.3 Hz,0.77H), 6.85-7.11 (m, 5H). ES-MS (m/z): calcd for C₂₉H₄₀NO₅ (M−H)⁻:482.7; found: 482.3.

Example 19 Enantiomer 2 of[(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid

A. Enantiomer 2 of[(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid methyl ester

Using a procedure analogous to Example 5, from enantiomer 2 of4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoicacid, Example 3B, (1.08 g, 2.62 mmol) to give the title compound (1.16g, 2.33 mmol, 89%).

¹H NMR & LC/MS: equivalent to Example 18A.

B. Enantiomer 2 of[(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid

Using a procedure analogous to Example 2, from enantiomer 2 of[(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid methyl ester (0.58 g, 1.16 mmol) gives the title compound (0.53 g,1.10 mmol, 95%). ¹H NMR & LC/MS: equivalent to Example 18B.

Example 20 A.2-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-2-methyl-propionicacid methyl ester

Using the procedure analogous to Example 5, from enantiomer 1 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid, Example 3A, (0.40 g, 0.97 mmol) and 2-aminoisobutyric acid methylester hydrochloride (0.15 g, 1.07 mmol) to furnish the title compound(0.36 g, 0.70 mmol, 72%). ¹H NMR (CDCl₃), δ 0.60 (t, J=7.6 Hz, 6H), 1.01(s, 9H), 1.64 (s, 6H), 2.01-2.09 (m, 4H), 2.17 (s, 3H), 2.40 (s, 3H),2.70 (d, J=9.0 Hz, 1H), 3.77 (s, 3H), 3.85 (t, J=9.1 Hz, 1H), 4.09 (d,J=9.6 Hz, 1H), 6.28 (s, 1H), 6.70 (dd, J=8.9, 2.6 Hz, 1H), 6.85 (s, 1H),6.93 (d, J=8.6 Hz, 1H), 6.95-7.02 (m, 2H), 7.27 (dd, J=7.9, 2.6 Hz, 1H).ES-MS (m/z): calcd. for C₃₁H₄₆NO₅ (M+H)⁺: 512.3; found: 512.3.

B.2-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-2-methyl-propionicacid

Enantiomer 1

Using a procedure analogous to Example 2, from enantiomer 1 of2-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-2-methyl-propionicacid methyl ester (0.36 g, 0.70 mmol) to furnish the titled compound(0.35 g, 0.70 mmol, 92%). ¹H NMR (CDCl₃), δ 0.59 (t, J=7.3 Hz, 6H), 1.01(s, 9H), 1.67 (s, 6H), 2.05 (q, J=7.3 Hz, 4H), 2.17 (s, 3H), 2.40 (s,3H), 3.70 (dd, J=8.7, 2.7 Hz, 1H), 3.86 (t, J=8.9 Hz, 1H), 4.09 (dd,J=9.1, 2.7 Hz, 1H), 6.28 (s, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.85 (d, J=2.3Hz, 1H), 6.93 (dd, J=8.5, 2.3 Hz, 1H), 6.98-7.03 (m, 2H), 7.26 (d, J=7.9Hz, 1H). ES-MS (m/z): calcd. for C₃₀H₄₄NO₅ (M+H)⁺: 498.3; found: 498.3.

Example 21 Preparation of4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzoicacid

A. 4-(Z/E-2-Penten-3-yl)-O-trifluoromethylsulfonyl-phenol

To a mixture of 4-(Z/E-2-penten-3-yl)phenol (7.45 g, 45.9 mmol), CH₂Cl₂(150 mL), and Tf₂O (13.4 g, 47.5 mmol) is added DIPEA (6.13 g, 47.5 mol)drop wise. After stirring overnight, the reaction is poured into icewater (100 mL) and separated. The organic layer is washed with coldwater (2×50 mL), Na₂SO₄ dried, filtered and concentrated to give thetitle compound as an oil (10.5 g, 78%) which is used as is.

B.4-[(1-Ethyl-1-(3-methyl-4-hydroxyphenyl)propyl]-O-trifluoromethylsulfonylphenol

To 4-(Z/E-2-penten-3-yl)-O-trifluoromethylsulfonyl-phenol (5.25 g, 17.8mmol) and O-cresol (7.7 g, 71.4 mmol) in CH₂Cl₂ (20 mL) at −20° C. isadded BF₃-Et₂O (240 μL, 1.9 mmol), and the mixture is allowed to come toRT and stirred 16 h. To the reaction is added ethylene glycol (5 mL),and the CH₂Cl₂ is evaporated under vacuum. The residue is vacuumdistilled up to 70° C. at 0.116 nm to remove the excess phenol andethylene glycol. The residue is partitioned between Et₂O (50 mL) andwater (50 mL). The organic layer is washed with water (3×50 mL),saturated brine, Na₂SO₄ dried, filtered and concentrated. The residue ischromatographed to give the title compound (3.9 g, 54%).

H-NMR ppm in CDCl₃: 7.24 (2H, d, J=9.0 Hz); 7.14 (2H, d, J=9.2 Hz); 6.84(1H, s); 6.83 (1H, d, J=8.0 Hz); 6.66 (1H, d, J=8.0 Hz); 4.70 (1H, s);2.20 (3H, s); 2.05 (4H, q, J=7.2 Hz); 0.61 (6H, t, J=7.2 Hz). LC-MS:401.1 (M−1).

C. 4-[(1-Ethyl-1-(3-methyl-4-hydroxyphenyl)propyl]-benzoic acid, methylester

Using a procedure analogous to Example 1E, from4-[(1-ethyl-1-(3-methyl-4-hydroxyphenyl)propyl]-O-trifluoromethylsulfonylphenol(2.5 g, 6.2 mmol) gives the title compound (1.08 g, 56%).

H-NMR ppm in CDCl₃: 7.89 (2H, d, J=8.0 Hz); 7.23 (2H, d, J=8.0 Hz); 6.84(1H, s); 6.83 (1H, d, J=8.2 Hz); 6.65 (1H, d, J=8.2 Hz); 4.58 (1H, s);3.89 (3H, s); 2.18 (3H, s); 2.08 (4H, q, J=7.2 Hz); 0.61 (6H, t, J=7.2Hz). LC/MS: 313.1 (M+1), 311.1 (M−1).

D.4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzoicacid methyl ester

Using a procedure analogous to Example 1B, from4-[(1-ethyl-1-(3-methyl-4-hydroxyphenyl)propyl]-benzoic acid, methylester (0.88 g, 2.81 mmol) gives the title compound (0.95 g, 2.32 mmol,95%). ¹H NMR (CDCL₃), δ 0.61 (t, J=7.4 Hz, 6H), 1.26 (s, 9H), 2.09 (q,J=7.4 Hz, 4H), 2.24 (s, 3H), 3.89 (s, 3H), 4.84 (s, 2H), 6.49 (d, J=8.8Hz, 1H), 6.85-6.89 (m, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.91 (d, J=9.4 Hz,2H). ES-MS (m/z): calcd for C₂₆H₃₈NO₄ (M+NH₄)⁺: 428.6; found: 428.3.

E.4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-benzoicacid methyl ester

Using a procedure analogous to Example 1D, from4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzoicacid methyl ester (0.94 g, 2.29 mmol) to give the title compound (0.93g, 2.26 mmol, 99%). ¹H NMR (CDCl₃), δ 0.62 (t, J=7.6 Hz, 6H), 1.02 (s,9H), 2.10 (q, J=7.6 Hz, 4H), 2.17 (s, 3H), 3.71 (dd, J=8.8, 2.9 Hz, 1H),3.86 (t, J=8.6 Hz, 1H), 3.90 (s, 3H), 4.09 (dd, J=9.3, 2.9 Hz, 1H), 6.71(d, J=8.3 Hz, 1H), 6.86 (d, J=2.1 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.94(d, J=2.6 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.6 Hz, 2H). ES-MS(m/z): calcd for C₂₆H₃₇O₄ (M+H)⁺: 413.6; found: 413.3.

F.4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}benzoicacid

Using a procedure analogous to Example 2, from4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-benzoicacid methyl ester (0.93 g, 2.25 mmol) gives the title compound (0.81mmol, 2.02 mmol, 90%). ¹H NMR (CDCl₃), δ 0.63 (t, J=7.2 Hz, 6H), 1.02(s, 9H), 2.12 (q, J=7.2 Hz, 4H), 2.18 (s, 3H), 3.71 (dd, J=8.7, 2.4 Hz,1H), 3.86 (t, J=9.3 Hz, 1H), 4.09 (dd, J=9.3, 2.4 Hz, 1H), 6.71 (d,J=8.3 Hz, 1H), 6.87 (d, J=1.9 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 6.95 (d,J=2.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H). ES-MS(m/z): calcd for C₂₅H₃₃O₄ (M−H)⁻: 397.6; found: 397.2.

G.4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzoicacid

Using a procedure analogous to Example 17, from4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}benzoicacid (0.31 g, 0.79 mmol) and Dess-Martin reagent (366 mg, 0.86 mmol)gives the title compound (0.27 g, 0.69 mmol, 88%). %). ¹H NMR (CDCl₃), δ0.62 (t, J=7.0 Hz, 6H), 1.27 (s, 9H), 2.10 (q, J=7.0 Hz, 4H), 2.24 (s,3H), 4.85 (s, 2H), 6.50 (d, J=9.1 Hz, 1H), 6.85-6.90 (m, 2H), 7.28 (d,J=8.1 Hz, 2H), 7.96 (d, J=8.2 Hz, 2H). ES-MS (m/z): calcd for C₂₅H₃₁O₄(M−H)⁻: 395.6; found: 395.2.

Example 22 and 23 Preparation of enantiomer 1 and 2 of4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}benzoicacid

A racemic mixture of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}benzoicacid (500 mg) is chromatographed (CHIRALPAK AD column, Heptane, 90%;EtOH, 9.5%, CH₃OH, 0.5%, TFA, 0.1%) to give enantiomer 1 (rt=7.4 m),Example 22 (231 mg, 46%) and enantiomer 2 (rt=9.4 m), Example 23 (230mg, 46%).

Example 22, (Enantiomer 1):

rt=7.4 m

NMR & LC/MS: Identical to the racemic material, Example 21F.

Example 23, (Enantiomer 2)

rt=9.4 m

NMR & LC/MS: Identical to the racemic material, Example 21F.

Example 24 Preparation of(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzoylamino)aceticacid

A. Methyl(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-2-methylbenzoylamino)acetate

Using a procedure analogous to Example 5, from4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoicacid (0.50 g, 1.22 mmol) and glycine methyl ester hydrochloride (0.15 g,1.22 mmol) give the title compound (0.587 g, 1.21 mmol, 99%).

¹H NMR (CDCl₃), δ 0.62 (t, J=7.5 Hz, 6H), 1.03 (s, 9H), 2.07 (q, J=7.5Hz, 4H), 2.19 (s, 3H), 2.43 (s, 3H), 3.71 (dd, J=8.8, 2.9 Hz, 1H), 3.80(s, 3H), 3.87 (t, J=8.8 Hz, 1H), 4.08-4.12 (m, 1H), 4.24 (d, J=5.4 Hz,1H), 6.26 (t, J=5.4 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.88 (d, J=2.0 Hz,1H), 6.94 (dd, J=8.5, 2.5 Hz, 1H), 6.99-7.04 (m, 2H), 7.32 (d, J=7.8 Hz,1H). ES-MS (m/z): calcd for C₂₉H₄₂NO₅ (M+H)⁺: 484.7; found: 484.2.

B.(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzoylamino)aceticacid

A mixture of methyl(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-2-methylbenzoylamino)acetate(0.43 g, 0.89 mmol), CH₃OH (10 ml), NaOH (0.18 g, 4.46 mmol), and H₂O (1mL) is refluxed for 2 h. The reaction is concentrated, diluted with H₂O(5 ml), acidified (pH 3-4) with 0.1 M HCl and extracted with EtOAc (3×15mL). The combined organic layers are MgSO₄ dried, and concentrated togive the title compound (0.29 g, 71%).

¹H NMR (CD₃OD), δ 0.66 (t, J=7.2 Hz, 6H), 1.05 (s, 9H), 2.15 (q, J=7.2Hz, 4H), 2.20 (s, 3H), 2.42 (s, 3H), 3.63-3.68 (m, 1H), 3.91 (dd,J=10.0, 7.8 Hz, 1H), 4.09 (s, 2H), 4.16 (dd, J=10.0, 2.9 Hz, 1H), 6.81(d, J=9.3 Hz, 1H), 6.86 (d, J=2.1 Hz, 1H), 7.02 (dd, J=8.4, 2.1 Hz, 1H),7.09 (s, 1H), 7.11 (s, 1H), 7.37 (d, J=8.1 Hz, 1H). ES-MS (m/z): calcdfor C₂₈H₄₀NO₅ (M+H)⁺: 470.6; found: 470.2.

Example 25A and Example 25B Preparation of enantiomer 1 and 2 of(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzoylamino)aceticacid

Enantiomer 1 Enantiomer 2

A racemic mixture of(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-propyl}-2-methylbenzoylamino)aceticacid (0.217 g), Example 24, is chromatographed (HPLC: ChiralPak AD, 0.1%TFA in 0.75:14.25:85 CH₃OH:EtOH:Hept) to give enantiomer 1 (80.6 mg,37%, rt=8.0 m) and enantiomer 2 (81.1 mg, 37%, rt=10.1 m).

(Enantiomer 1), Example 25A:

HPLC: ChiralPak AD (4.6×250 mm); 0.1% TFA in 0.75:14.25:85CH₃OH:EtOH:Hept; 1.0 mL/m (flow rate); rt=8.0 m; (280 nm; 97.8% ee.

NMR & LC/MS: equivalent to the racemate, Example 24.

(Enantiomer 2), Example 25B:

HPLC: ChiralPac AD (4.6×250 mm); 0.1% TFA in 0.75:14.25:85CH₃OH:EtOH:Hept; 1.0 mL/m (flow rate); rt=10.1 m; @ 280 nm; 95.2% ee.

NMR & LC/MS: equivalent to the racemate, Example 24.

Example 26 Preparation enantiomer 1 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 5, enantiomer 1 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentaneand 5-aminotetrazole give the title compound (440 mg, 95%).

NMR 300 mHz (DMSO): 0.57 (t, J=7.3 Hz, 6H), 0.92 (s, 9H), 2.09 (m, 7H),2.40 (s, 3H), 3.46 (m, 1H), 3.76 (dd, J=7.3, 10.2 Hz, 1H), 4.03 (dd,J=3.3, 10.2 Hz, 1H), 4.79 (d, J=5.5 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H),6.89 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.12 (s,1H), 7.52 (d, J=8.1 Hz, 1H), 12.23 (s, 1H), 16.00 (br s, 1H).

High Res. ES-MS: 480.2983; calc. for C₂₇H₃₇N₅O₃+H, 480.2975.

Example 27 Preparation enantiomer 2 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 5, enantiomer 2 of3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentaneand 5-aminotetrazole gives the title compound (385 mg, 83%).

NMR 300 mHz (DMSO): eq. to enantiomer of 1.

High Res. ES-MS: 480.2968; calc. for C₂₇H₃₇N₅O₃+H, 480.2975.

Preparation of4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid

Using a procedure analogous to Example 2, from racemic4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid methyl ester, Example 10C, (4.70 g, 10.68 mmol) gives the titlecompound (2.93 g, 6.87 mmol, 64%).

¹H NMR and ES-MS: equivalent to the pure enantiomer 1, Example 11.

Example 29 Preparation enantiomer 1 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 5, enantiomer 1 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane,Example 11, and 5-aminotetrazole give the title compound (125 mg, 72%).

¹H NMR 400 MHz (DMSO-d₆): δ 0.57 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 1.20(d, J=6.3 Hz, 3H), 2.07 (m, 7H), 2.41 (s, 3H), 3.07 (br s, 1H), 4.37 (brs, 1H), 4.57 (q, J=5.8, 1H), 6.87 (m, 3H), 7.06 (d, J=7.8 Hz, 1H), 7.15(s, 1H), 7.50 (d, J=7.8 Hz, 1H), 12.24 (s, 1H), 16.0 (s, 1H).

High Res ES (+) MS m/z: 494.3127; calc. for C₂₈H₃₉N₅O₃+H, 494.3131.

Example 30 Preparation enantiomer 2 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(tetrazol-5-ylaminocarbonyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 5, enantiomer 2 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane,Example 12, and 5-aminotetrazole give the title compound (150 mg, 74%).

High Res ES (+) MS m/z: 494.3144; calc. for C₂₈H₃₉N₅O₃+H, 494.3131.

Example 31 Preparation enantiomer 1 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(carboxymethylaminocarbonyl)-3-methylphenyl]pentane

A. Enantiomer 1 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 5, enantiomer 1 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane,methyl glycinate hydrochloride, and DMAP (2.5 eq) give the titlecompound (150 mg, 86%).

¹H NMR 400 MHz (DMSO-d₆): δ 0.55 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 1.20(d, J=5.9 Hz, 3H), 1.98-2.07 (m, 7H), 2.32 (s, 3H), 3.07 (s, 1H), 3.65(s, 3H), 3.93 (d, J=6.3 Hz, 2H), 4.36 (br s, 1H), 4.55 (q, J=7.2 Hz,1H), 6.80-6.84 (m, 2H), 6.89 (d, J=8.3 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H),7.05 (s, 1H), 7.24 (d, J=8.3 Hz, 1H), 8.61 (t, J=5.9 Hz, 1H).

High Res ES (+) MS m/z: 498.3224; calc. for C₃₀H₄₃NO₅+H, 498.3219.

B. Enantiomer 1 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(carboxymethylaminocarbonyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 2 but reacted at RT, enantiomer 1of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentanegives the title compound (130 mg, 99%).

¹H NMR 400 MHz (DMSO-d₆): δ 0.55 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 1.20(d, J=5.9 Hz, 3H), 1.98-2.07 (m, 7H), 2.32 (s, 3H), 3.07 (s, 1H), 3.84(d, J=5.8 Hz, 2H), 4.37 (br S, 1H), 4.56 (q, J=6.3 Hz, 1H), 6.80-6.84(m, 2H), 6.89 (dd, J=2.4, J=8.3 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 7.04(s, 1H), 7.25 (d, J=7.8 Hz, 1H), 8.48 (t, J=5.9 Hz, 1H)

High Res ES (+) MS m/z: 484.3041; calc. for C₂₉H₄₁NO₅+H, 484.3063.

Example 32 Preparation enantiomer 2 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(carboxymethylaminocarbonyl)-3-methylphenyl]pentane

A. Enantiomer 2 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 5, enantiomer 2 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane,methyl glycinate hydrochloride, and DMAP (2.5 eq) give the titlecompound (160 mg, 78%).

NMR equivalent to Example 31A.

High Res ES (+) MS m/z: 498.3200; calc. for C₃₀H₄₃NO₅+H, 498.3219.

B. Enantiomer 2 of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(carboxymethylaminocarbonyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 2 but reacted at RT, enantiomer 2of3′-[4-(2-hydroxy-1,3,3-trimethylbutoxy)-3-methylphenyl]-3′-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentanegives the title compound (145 mg, quant).

NMR equivalent to Example 31B.

High Res ES (+) MS m/z: 484.3080; calc. for C₂₉H₄₁NO₅+H, 484.3063.

Example 33 Preparation of enantiomer 1 of(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyloxy)-aceticacid

A. Enantiomer 1 of4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-benzoicacid methyl ester

Using a procedure analogous to Example 13A, from enantiomer 1 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid methyl ester (1.90 g, 4.45 mmol to furnish the title compound (2.40g, 4.45 mmol, >99%).

¹H NMR & ES-MS: equivalent to (Example 13A).

B. Enantiomer 1 of[4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-methanol

Using a procedure analogous to 13B, from enantiomer 1 of4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-benzoicacid methyl ester (2.40 g, 4.45 mmol) to furnish the title compound(2.10 g, 4.09 mmol, 91%).

¹H NMR & ES-MS: equivalent to (Example 13B).

C.[4-(1-4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl-1-ethyl-propyl)-2-methyl-benzyloxy]-aceticacid methyl ester

To a solution of enantiomer 1 of[4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-methanol,(2.10 g, 4.10 mmol) and PhCH₃ (10 mL) is added methyl glycolate (6.5 mL,81.89 mmol) and MeReO₃ (0.02 g, 0.082 mmol). The solution is heated at areflux for 2 hours with the use of a Dean-Stark trap. The solution isconcentrated and chromatographed to give the title compound (0.96 g,1.64 mmol, 40%).

¹H NMR (CDCl₃), δ 0.06 (s, 3H), 0.11 (s, 3H), 0.61 (t, J=7.3 Hz, 6H),0.90 (s, 9H), 0.97 (s, 9H), 2.05 (q, J=7.3 Hz, 4H), 2.18 (s, 3H), 2.33(s, 3H), 3.67 (dd, J=5.7, 3.2 Hz, 1H), 3.77 (s, 3H), 3.85 (dd, J=9.7,5.7 Hz, 1H), 3.98 (dd, J=9.7, 3.5 Hz, 1H), 4.12 (s, 2H), 4.60 (s, 2H),6.65 (d, J=8.4 Hz, 1H), 6.87 (d, J=2.1 Hz, 1H), 6.92 (dd, J=8.4, 2.6 Hz,1H), 6.97-7.01 (m, 2H), 7.17 (d, J=8.4 Hz, 1H).).

D. Enantiomer 1 of(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyloxy)-aceticacid

To a solution of enantiomer 1 of[4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-benzyloxy]-aceticacid methyl ester (0.96 g, 1.64 mmol) and THF (10 mL) is added 1M TBAF(3.3 mL, 3.28 mmol). The solution is heated at a reflux overnight andconcentrated. The residue is dissolved in MeOH (5 mL) and water (1 mL),NaOH (0.33 g, 8.21 mmol) is added and the solution is heated at refluxfor 3 hours. The solution is concentration, dissolved in EtOAc (20 mL),washed with 1M HCl (15 mL), water (15 mL), brine (15 mL), dried overMgSO₄, and concentrated. The residue is chromatographed to furnish thetitle compound (0.45 g, 0.99 mmol, 60%).

¹H NMR (CDCl₃), δ 0.60 (t, J=7.3 Hz, 6H), 1.02 (s, 9H), 2.05 (q, J=7.3Hz, 4H), 2.17 (s, 3H), 2.31 (s, 3H), 3.71 (dd, J=8.8, 2.6 Hz, 1H), 3.86(t, J=8.8 Hz, 1H), 4.09 (dd, J=8.8, 2.6 Hz, 1H), 4.13 (s, 2H), 4.62 (s,2H), 6.70 (d, J=8.3 Hz, 1H), 6.90-7.02 (m, 4H), 7.16 (d, J=7.5 Hz, 1H).

ES-MS (m/z): calcd. for C₂₈H₄₁O₆ (M−H)⁻: 455.6; found: 455.2.

Example 34 Preparation of epimer 1 ofD-2-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid

A. Epimer 1 ofD-2-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid methyl ester D-Epimer 1

Using a procedure analogous to Example 5, from enantiomer 1 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid (0.40 g, 0.97 mmol) and D-alanine methyl ester hydrochloride (0.15g, 1.07 mmol) to furnish the title compound (0.36 g, 0.72 mmol, 75%).

¹H NMR (CDCl₃), δ 0.60 (t, J=7.2 Hz, 6H), 1.00 (s, 9H), 1.49 (d, J=7.1Hz, 3H), 2.05 (q, J=7.2 Hz, 4H), 2.17 (s, 3H), 2.40 (s, 3H), 3.69 (dd,J=8.5, 2.7 Hz, 1H), 3.76 (s, 3H), 3.84 (t, J=9.1 Hz, 1H), 4.07 (dd,J=9.1, 2.5 Hz, 1H), 4.72-4.81 (m, 1H), 6.42 (d, J=7.9 Hz, 1H), 6.68 (d,J=8.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.92 (dd, J=8.4, 2.4 Hz, 1H),6.96-7.01 (m, 2H), 7.28 (d, J=8.1 Hz, 1H).

ES-MS (m/z): calcd. for C₃₀H₄₄NO₅ (M+H)⁺: 498.3; found: 498.3.

B. Epimer 1 ofD-2-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid

Using a procedure analogous to Example 2, from epimer 1 ofD-2-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid methyl ester (0.36 g, 0.72 mmol) to furnish the titled compound(0.31 g, 0.64 mmol, 89%).

¹H NMR (CDCl₃), δ 0.60 (t, J=7.5 Hz, 6H), 1.01 (s, 9H), 1.50 (d, J=7.3Hz, 3H), 2.05 (q, J=7.5 Hz, 4H), 2.17 (s, 3H), 2.41 (s, 3H), 3.71 (dd,J=8.4, 2.5 Hz, 1H), 3.85 (t, J=8.9 Hz, 1H), 4.09 (dd, J=9.3, 2.7 Hz,1H), 4.74-4.83 (m, 1H), 6.33 (d, J=7.8 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H),6.85 (d, J=2.2 Hz, 1H), 6.93 (dd, J=8.2, 2.2 Hz), 6.98-7.03 (m, 1H),7.01 (s, 1H), 7.30 (d, J=8.0 Hz, 1H).

ES-MS (m/z): calcd. for C₂₉H₄₂NO₅ (M+H)⁺: 484.3; found: 484.3.

Example 35 Preparation of racemic3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[4-carboxyphenyl]pentane

A. 3-(3-Chloro-4-hydroxyphenyl)-3-pentanol

To a solution of methyl 3-chloro-4-hydroxybenzoate (25.0 g, 133 mmol) inTHF (250 mL) is added dropwise 1.0 M ethylmagnesium bromide/THF (442 mL,442 mmol) at a rate maintaining the temperature below 27° C. Thebrownish grey reaction is stirred for 72 h. The reaction mixture iscooled in an ice bath and quenched with satd ammonium chloride (1 mlportions) until evolution of ethane subsides. Additional satd NH4Clsolution is added (total of 50 mL) and the mixture is concentrated toremove most of the THF. The residue is added to water and ether,filtered through diatomaceous earth, and partitioned. The organic layeris washed with brine (3×), MgSO4 dried, and concentrated to give thetitle compound (28.6 g, 99%).

H-NMR (300 mHz, CDCl3): δ 7.38 (1H, d, J=1.6 Hz), 7.07 (1H, dd, J=8.4Hz, J=1.6 Hz), 6.95 (1H, d, J=8.4 Hz), 5.53 (1H, br s), 1.80 (4H, m),0.76 (6H, t, J=7.6 Hz).

IR (CHCl₃): 3600 cm⁻¹, 3540 cm⁻¹.

EI (+) TOF MS: Observed m/z 214.076; Calc. m/z. 214.0761

B. [E,Z]-3-(3-Chloro-4-hydroxyphenyl)-3-pentene

A mixture of 3-(3-chloro-4-hydroxyphenyl)-3-pentanol (10.0 g, 46.5mmol), pTSA monohydrate (20 mg, catalytic amount), and toluene (300 mL)is heated on a steam bath for 3 h. Analysis by TLC indicates the loss ofstarting material and formation of a much less polar compound. Thetoluene solution is cooled to RT, washed with satd sodium carbonatesolution (25 mL), MgSO4 dried, and concentrated to give the titlecompounds as a [E:Z] isomeric mixture of [85:15] (9.2 g, quant).

TLC(CHCl3): Rf˜0.7

H-NMR (300 mHz, DMSO-d6): δ 6.85-7.30 (3H, m), 5.65 (0.85H, q, J=6.8Hz), 5.43 (0.15H, q, J=6.8 Hz), 2.43 ((1.7H, q, J=7.6 Hz), 2.28 (0.3H,q, J=7.6 Hz), 1.72 (2.55H, d, J=7.6 Hz), 1.52 (0.45H, d, J=7.6 Hz), 0.90(2.55H, t, J=7.6 Hz) 0.85 (0.45H, t, J=7.6 Hz).

C. [E,Z]-3-[3-Chloro-4-(2-oxo-3,3-dimethylbutoxy)phenyl]-3-pentene

A mixture of [E,Z]-3-(3-chloro-4-hydroxyphenyl)-3-pentene (4.00 g, 20.3mmol) and 1-chloropinacolone (2.73 g, 20.3 mmol), anhydrous KI (0.17 g,1.0 mmol), K2CO3 (14.0 g, 102 mmol) and acetonitrile (80 mL) is refluxedfor 3 h. The reaction is cooled to RT and concentrated. The residue ispartitioned between methylene chloride (50 mL) and ice water (50 mL).The organic layer is MgSO4 dried, concentrated, and chromatographed (40%to 70% chloroform in hexane) to give the title compounds as an 85:15 [E.Z] mixture (5.07 g, 85%).

H-NMR (300 mHz, DMSO-d6): δ 7.37 (0.85H, d, J=2.1 Hz), 7.22 (0.85H, dd,J=2.1, J=8.6 Hz), 7.18 (0.15H, d, J=2.1 Hz), 7.03 (0.15H, dd, J=2.0 Hz,J=8.4 Hz), 6.88 (0.15H, d, J=8.4 Hz), 6.85 (0.85H, d, J=8.6 Hz), 5.71(0.85H, m), 5.52 (0.15H, m), 5.25 (2H, s), 2.45 (1.70H, q, J=7.6 Hz),2.30 (0.30H, q, J=7.6 Hz), 1.75 (2.55H, d, J=7.6 Hz), 1.53 (0.45H, d,J=7.6 Hz), 1.17 (9H, s), 0.91 (2.55H, t, J=7.6 Hz), 9.88 (0.45H, t,J=7.6 Hz).

EI (+) TOF MS: Observed m/z 294.139; Calc. m/z 294.1387.

D.3′-[3-Chloro-4-(2-oxo-3.3-dimethylbutoxy)phenyl]-3′-(4-hydroxyphenyl)pentane.

A −20° C. solution of[E,Z]-3-[3-chloro-4-(2-oxo-3,3-dimethylbutoxy)phenyl]-3-pentene (4.5 g,15.2 mmol), phenol (17.2 g, 183 mmol) and methylene chloride (30 mL) istreated with BF3-etherate (0.863 g, 6.1 mmol) and stirred for 30 m whilemaintaining the temperature near −20° C. The resulting light reddishbrown solution is allowed to warm to 0° C. and kept at that temperaturefor 16 h. The reaction is distilled at 45° C./0.04 mm to remove most ofthe excess phenol. The residue is treated with powderized NaHCO3 (600mg), ethylene glycol (15 ml), and distilled to remove the last of thephenol and almost all of the glycol. The resulting viscous tan oilyresidue is cooled to RT and distributed between sat NaHCO3 (25 mL) andethyl acetate (200 mL). The organic layer is separated, washed withwater (5×50 mL), Na2SO4 dried, and concentrated to give the titlecompound as an oil (5.8 g, 98%).

¹H-NMR (300 mHz, CDCl3): 7.21 (1H, d, J=2.3 Hz), 6.99 (2H, d, J=8.7 Hz),6.95 (1H, dd, J=2.3 Hz, J=8.6 Hz), 6.75 (2H, d, J=8.7 Hz), 6.62 (1H, d,J=8.6 Hz), 4.91 (2H, s), 4.86 (1H, s), 2.02 (4H, q, J=7.3 Hz), 1.28 (9H,s), 0.62 (6H, t, J=7.3 Hz).

ES (+) MS m/z: 389.3 [M+H]; calc. m/z 389.1883 [M+H].

E.3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)]-3′-(4-trifluoromethylsulfonyloxyphenyl)pentane

Using a procedure analogous to Example 1C with isopropyldiethylamine asthe base, allowing the reaction to warm from 0 to RT overnight, and withpotassium phosphate monobasic/sodium hydroxide buffer quench,3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)phenyl]-3′-(4-hydroxyphenyl)pentaneand triflic anhydride give the title compound as a colorless oil (3.7 g,69%).

H-NMR (300 mHz, DMSO-D6): δ 7.40 (2H, d, J=8.7 Hz), 7.33 (2H, d, J=8.7Hz), 7.15 (1H, d, J=2.1 Hz), 6.98 (1H, dd, J=2.1 Hz, J=8.6 Hz), 6.78(2H, d, J=8.6 Hz), 5.22 (2H, s), 2.07 (4H, q, J=7.3 Hz), 1.17 (9H, s),0.55 (6H, t, J=7.3 Hz).

FAB+MS m/z: 521.0 [M+H]; calc. 521.1376 [M+H].

ES MS: 521.3 [M+1], 538.3 [M+NH4], 543.2 [M+Na].

F.3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-chloro-phenyl]-3′-4-carbomethoxyphenyl)-pentane

To3′-[4-(2-oxo-3,3-dimethylbutoxy)-3-chlorophenyl]-3′-(4-trifluoromethyl-sulfonyloxy-phenyl)-pentane(3.7 g 7.1 mmol), palladium acetate (64 mg, 0.28 mmol), dppf (315 mg,0.28 mmol), and triethylamine (4 mL) are heated in the absence of airunder an atmosphere of carbon monoxide (initial 100 psig) in DMF (20 mL)and methanol (2 mL) at 110° C. for 48 h. The reaction mixture is cooledto room temperature, vented, and filtered. The filtrate is partitionedbetween EtOAc and water. The organic phase is washed 3 times with water,once with sat brine, dried over anhydrous Na2SO4, and concentrated undervacuum. The residue is chromatographed on 10 g silica gel with 8% EtOAcin hexanes to give the title compound (1.12 g, 37%).

H-NMR (400 mHz, CDCl₃): δ 7.91 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8Hz), 7.16 (1H, s), 6.88 (1H, d, J=8.8 Hz), 6.59 (1H, d, J=8.8 Hz), 4.90(2H, s), 3.89 (3H, s), 2.07 (4H, q, J=7.2 Hz), 1.25 (9H, s), 0.61 (6H,t, J=7.2 Hz).

FAB (+) MS m/z [M]: 431.1; calc. m/z 431.3.

ES (+) MS: m/z 431.3 [M+H], 448.3 [M+NH4].

G. Racemic3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[4-carbomethoxyphenyl]pentane

A solution of3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-chloro-phenyl]-3′-(4-methoxycarbonyl-phenyl)-pentane(0.825 g, 1.91 mmol) in MeOH (10 mL) under a N2 atmosphere is cooled to0° C. Sodium borohydride (0.076 g, 2.01 mmol) is added in one portionand the reaction mixture is stirred for 15 minutes. Acetone (1 mL)followed by potassium phosphate monobasic/sodium hydroxide buffer (3 mL)are added and the resulting mixture is concentrated to remove most ofthe MeOH. The residue is distributed into water and CH₂Cl₂ and theorganic layer is separated and dried over anhydrous MgSO4. The desiredproduct is obtained as a colorless oil, (0.816 g, 98.5%).

H-NMR (300 mHz, CDCl3): δ 7.92 (2H, d, J=8.8 Hz), 7.22 (2H, m), 7.15(1H, d, J=2.3), 6.93 (1H, dd, J=2.3 Hz, J=8.8 Hz), 6.84 (1H, d, J=8.8Hz), 4.17 (1H, dd, J=2.6 Hz, J=9.0 Hz), 3.89 (s, 3H), 3.87 (t, J=8.9Hz,), 3.62 (1H, dt, J=2.6, J=8.9, J=3.0), 2.60, (1H, d, J=3.0 Hz), 2.09(4H, q, J=7.3 Hz), 1.01 (9H, s), 0.61 (6H, t, J=7.3 Hz).

FAB (+) MS m/z [M]: 432.2; calc. for C25H33ClO4: m/z 432.2.

IR(CHCl3): 1718 cm⁻¹.

H. Racemic3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[4-carboxyphenyl]pentane,sodium salt

The methyl ester of3′-[3-chloro-4-(2-hydroxy-3,3-dimethyl-butoxy)phenyl]-3′-[4-(carboxy)phenyl]pentane(0.600 g, 1.38 mmol) and 2N NaOH (3.46 mL, 6.93 mmol) are refluxed inEtOH (15 mL) under a N2 atmosphere for 1 h. TLC (SiO2; CHCl3) shows theloss of the starting material and appearance of a more polar compoundspot near the origin. The reaction is allowed to cool to near RT andsubsequently it is concentrated under reduced pressure to remove EtOHand provide a white residue. The residue is dissolved in a minimumamount of hot water (approx. 20 mL) and cooled and scratched to providethe desired sodium salt as white crystals (0.582 g, 96%).

H-NMR (300 mHz, DMSO): δ 7.73 (2H, d, J=8.7 Hz), 7.00 to 7.06 (5H, m),4.88 (1H, d, J=5.1 Hz), 4.10 (1H, dd, J=3=3.0 Hz, J=10.2 Hz), 3.86 (1H,dd, J=3.1 Hz, J=10.2 Hz), 3.47 (1H, m), 2.04 (4H, q, J=7.3 Hz), 0.92(9H, s), 0.55 (6H, t, J=7.3 Hz).

ES (+) MS m/z 436.2 [M+NH4], 441.1 [M+Na].

ES (−) MS m/z 417.2 [M−H].

IR(CHCl3): 1601 cm⁻¹.

I. Racemic3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[4-carboxyphenyl]pentane

A portion of the above3′-[3-chloro-4-(2-hydroxy-3,3-dimethyl-butoxy)phenyl]-3′-[4-(carboxy)phenyl]pentane,sodium salt (0.182 g, 0.413 mmol) is dissolved in 50 ml of hot water.After the solution is allowed to cool to near to RT it is acidified withdropwise addition of 5N HCl. The resulting white precipitate iscollected and washed with ice water and subsequently vacuum dried toprovide the desired free acid (0.169 g, 98%).

H-NMR (300 mHz, DMSO): δ 7.85 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3)7.00 to 7.1 (3H, m), 4.85 (1H, d, J=5.1 Hz), 4.11 (1H, dd, J=3.0 Hz,J=10.2 Hz), 3.87 (1H, dd, J=3.1 Hz, J=10.2 Hz), 3.47 (1H, m), 2.08 (4H,q, J=7.3 Hz), 0.94 (9H, s), 0.56 (6H, t, J=7.3 Hz).

ES (+) MS: 436.2 [M+NH4], 441.1 [M+Na].

ES (−) MS: 417.2 [M−1].

IR(CHCl₃): 1691 cm⁻¹.

Example 36 and 37 Separation of optical isomers of3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[4-carboxyphenyl]pentane

A racemic mixture of the Na salt of3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-4-carboxyphenyl)pentane(350 mg) is chromatographed with a Chiralpak AD column to giveenantiomer 1, Example 36 (120 mg, 36%) and enantiomer 2, Example 37 (117mg, 35%).

Example 36, Enantiomer 1

HPLC: Chiralpak AD (4.6×150 mm); 100% 3A Alcohol; 0.6 mL/m (flow rate);rt=7.3 m; 240 nm; ee 99.7% by HPLC.

H-NMR (300 mHz, DMSO): δ 7.85 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3)7.00 to 7.12 (3H, m), 4.85 (1H, d, J=5.1 Hz), 4.11 (1H, dd, J=3.0 Hz,J=10.2 Hz), 3.87 (1H, dd, J=3.1 Hz, J=10.2 Hz), 3.47 (1H, m), 2.08 (4H,q, J=7.3 Hz), 0.94 (9H, s), 0.56 (6H, t, J=7.3 Hz).

ES (+) MS: 436.2 [M+NH4], 441.1 [M+Na]

ES (−) MS: 417.2 [M−1].

Example 37, Enantiomer 2

HPLC: Chiralpak AD (4.6×150 mm); 100% 3A Alcohol; 0.6 mL/m (flow rate);rt=10.5 m; 240 nm; ee 99.0% by HPLC.

H-NMR (300 mHz, DMSO): δ 7.85 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3)7.00 to 7.12 (3H, m), 4.85 (1H, d, J=5.1 Hz), 4.11 (1H, dd, J=3.0 Hz,J=10.2 Hz), 3.87 (1H, dd, J=3.1 Hz, J=10.2 Hz), 3.47 (1H, m), 2.08 (4H,q, J=7.3 Hz), 0.94 (9H, s), 0.56 (6H, t, J=7.3 Hz).

ES (+) MS: 436.2 [M+NH4], 441.1 [M+Na].

ES (−) MS: 417.2 [M−1].

Example 38 Preparation of racemic3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carboxy)phenyl]pentane

A. [E,Z]-3-[3-Chloro-4-(trifluoromethylsulfonyloxy)phenyl)-3-pentene

Using a procedure analogous to Example 1C,[E,Z]-3-(3-chloro-4-hydroxyphenyl)-3-pentene, triflic anhydride, anddiisopropylethylamine are reacted at RT for 3 h to give the titlecompound as a yellow oil in a [E:Z] ratio of 9:1 (16.7 g, 98%).Chromatography over silica gel using 10% chloroform in hexane as theeluent provided 11.72 g (71. %) of purified material.

H-NMR (300 mHz, CDCl₃): δ 7.01-7.39 (3H, m), 5.70 (0.9H, q, J=6.9 Hz),5.53 (0.1H, q, J=6.9 Hz), 2.41 ((1.8H, q, J=7.6 Hz), 2.24 (0.2H, q,J=7.6 Hz), 1.74 (2.7H, d, J=7.6 Hz), 1.48 (0.3H, d, J=7.6 Hz), 0.91(2.7H, t, J=7.6 Hz)), 0.89 (0.3H, t, J=7.6 Hz).

ES GC MS m/z 328.0; Calc. for C12H12ClF3O3S m/z 328.0148.

B.3′-(4-hydroxy-3-methylphenyl)-3′-[3-chloro-4-(trifluoromethylsulfonyloxy)-phenyl]pentane

Using a procedure analogous to Example 35D,[E,Z]-3-[3-chloro-4-(trifluoromethylsulfonyloxy)phenyl]-3-pentene ando-cresol are reacted at RT overnight to give the title compound as apale tan oil (4.29 g, 38%).

H-NMR (300 mHz, CDCl₃): 6.5 to 7.3 (6H, m) 4.57 (1H, s), 2.21 (3H, s),2.05 (4H, q, J=7.3 Hz), 0.62 (6H, t, J=7.3 Hz).

ES (−) MS m/z 435.1 [M−H].

C.3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)-phenyl]-3′-[3-methyl-4-(trifluoromethylsulfonyloxy)phenyl]pentaneTriflate Rearrangement Procedure

Using a procedure analogous to Example 35C,3′-(3-chloro-4-hydroxyphenyl)-3′-[3-methyl-4-(trifluoromethylsulfonyloxy)phenyl]pentane,1-chloropinacolone, anhydrous KI, and K2CO3 are reacted in acetonitrileto give the title compound (2.61 g, 53%) following chromatographies (30%to 50% chloroform/Hex; Hex to 10% EtOAc/Hex).

H-NMR (300 mHz, CDCl₃): δ 7.15 (1H, d, J=2.3 Hz), 7.11 (1H, d, J=8.4Hz), 7.04 (1H, d, J=2.3 Hz), 7.02 (1H, dd, J=2.3 Hz, J=8.4 Hz), 6.89(1H, dd, J=8.6 Hz, J=2.3 Hz), 6.62 (1H, d, J=8.6 Hz), 4.91 (2H, s), 2.32(3H, s), 2.03 (4H, q, J=7.2 Hz), 1.26 (9H, s), 0.60 (6H, t, J=7.2 Hz).

ES (+) MS m/z, [M+NH4]: 552.2.

Further NMR data: COSY data allowed the spin systems of the two aromaticrings to be grouped together. When the OCH2 was selectively excited, aNOE is observed with a resonance at 6.62 δ which is ortho only coupled.When the aromatic methyl (at 2.32 δ) was excited, a NOE is observed to ameta coupled proton at 7.04 δ. These resonances are not part of the samespin system, requiring the OCH2 and aromatic methyl to be on differentrings. Therefore the triflate has migrated during the reaction and theisolated product has the structure shown above. (HMBC data also supportsthis conclusion.)

D.3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carbomethoxy)phenyl]pentane

Using a procedure analogous to Example 35F,3′-[3-chloro-4-(2-oxo-3.3-dimethylbutoxy)-phenyl]-3′-[3-methyl-4-(trifluoromethylsulfonyl-oxy)phenyl]pentane,MeOH, dppb, DMSO, Et3N, and Pd(OAc)₂ under an atmosphere of CO arereacted to provide the title compound as a colorless oil (938 mg, 73%).

H-NMR (300 mHz, CDCl3): δ 7.82 (1H, d, J=8.8 Hz), 7.20 (1H, d, J=2.3Hz), 7.03-7.05 (2H, m), 6.92 (1H, dd, J=2.3 Hz, J=8.6 Hz), 6.63 (1H, d,J=8.6 Hz), 4.92 (2H, s), 3.89 (3H, s), 2.57 (3H, s), 2.08 (4H, q, J=7.3Hz), 1.27 (9H, s), 0.63 (6H, t, J=7.3 Hz).

ES (+) MS m/z: 462.4 [M+NH4].

FAB (+) MS m/z [M+H]: 445.2; cale. m/z 445.1.

E. Racemic3′-[3-chloro-4-(2-hydroxy-3.3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carbomethoxy)phenyl]pentane

Using a procedure analogous to Example 35G,3′-[3-chloro-4-(2-oxo-3,3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carbomethoxy)phenyl]pentanewas reduced by NaBH4 to provide the title compound as a colorless oil(735 mg, 98%).

H-NMR (300 mHz, CDCl3): δ 7.89 (1H, d, J=8.8 Hz), 7.13 (1H, d, J=1.78Hz), 7.00 (2H, m), 6.93 (1H, dd, J=2.2 Hz, J=8.8 Hz), 6.80 (1H, d, J=8.8Hz), (4.17 (1H, dd, J=2.6 Hz, J=9.0 Hz), 3.86 (1H, m), 3.85 (3H, s),3.74 (1H, m), 2.60, (1H, d, J=3.0 Hz), 2.54 (3H, s), 2.06 (4H, q, J=7.3Hz), 1.01 (9H, s), 0.61 (6H, t, J=7.3 Hz).

FAB (+) MS m/z [M+H]: 447.1; calc m/z 447.2.

IR (CHCl₃): 1717 cm⁻¹.

F. Racemic3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carboxy)phenyl]pentane

Using a procedure analogous to Example 35H&I, racemic3′-[3-chloro-4-(2-hydroxy-3.3-dimethylbutoxy)phenyl]-3′-[3-methyl-4-(carbomethoxy)-phenyl]pentanewas saponified by aqueous NaOH in EtOH to form the Na salt correspondingto the desired compound. After removal of the EtOH under reducedpressure, the residue containing the Na salt was dissolved in water andacidified in a manner analogous to the procedure of Example CDJ-3 toprovide the title compound as a white solid (470 mg, 97%).

H-NMR (300 mHz, DMSO): δ 7.72 (1H, d, J=8.0 Hz), 7.00 to 7.10 (5H, m),4.84 (1H, d, J=5.6 Hz), 4.09 (1H, dd, J=2.8 Hz, J=10.4 Hz), 3.85 (1H,dd, J=7.0 Hz, J=10.4 Hz), 3.45 (1H, m), 2.47 (3H, s), 2.06 (4H, q, J=7.3Hz), 0.91 (9H, s), 0.55 (6H, t, J=7.3 Hz).

ES (+) MS m/z 450.2 [M+NH4], 455.2 [M+Na].

ES (−) MS m/z 431.1 [M−1].

IR (CHCl3): 1689 cm⁻¹.

Example 39 Preparation of Racemic3′-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane

A. [E,Z]-3-[3-Chloro-4-carbomethoxyphenyl)-3-pentene

Using a procedure similar to Example 35F, a mixture of[E,Z]-3-[3-chloro-4-(trifluoromethylsulfonyloxy)phenyl)-3-pentene, MeOH,dppb, DMSO (instead of DMF), Et3N, and Pd(OAc)2 under an atmosphere ofCO at 80° C. for 4 h are reacted to provide the title compound as acolorless liquid in a [E:Z] ratio of 9:1 (1.99 g, 92%).

H-NMR (300 mHz, CDCl₃): δ 7.06-7.85 (3H, m), 5.85 (0.9H, q, J=6.9 Hz),5.60 (0.1H, q, J=6.9 Hz), 3.94 (0.3H, s), 3.93 (2.7H, s), 2.50 (1.8H, q,J=7.6 Hz), 2.32 (0.2H, q, J=7.6 Hz), 1.82 (2.7H, d, J=7.6 Hz), 1.53(0.3H, d, J=7.6 Hz), 0.97 (2.7H, t, J=7.6 Hz), 0.94 (0.3H, t, J=7.6 Hz).

IR (CHCl₃): 1726 cm⁻¹.

ES GC MS m/z 238.1, M+; Calc. C13H15ClO2 m/z 238.1.

B.3′-(4-hydroxy-3-methylphenyl)-3′-[3-chloro-4-carbomethoxyphenyl]pentane

Using a procedure analogous to Example 35D,[E,Z]-3-[3-chloro-4-carbomethoxyphenyl)-3-pentene and o-cresol arereacted at RT overnight to give the title compound as a thick, paleyellow oil (3.54 g, 99%).

H-NMR (300 mHz, CDCl3): δ 7.74 (1H, d, J=8.2 Hz), 7.29 (1H, d, J=1.7Hz), 7.08 (1H, dd, J=1.7 Hz, J=8.2 Hz), 6.81 (2H, m), 6.63 (1H, d, J=8.9Hz), 3.91 (3H, s), 2.20 (3H, s), 2.09 (4H, q, J=7.3 Hz), 1.27 (9H, s),0.70 (6H, t, J=7.3 Hz).

ES (+) MS m/z 347.1 [M+1].

IR (CHCl3): 1725 cm⁻¹.

C.3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-methyl-phenyl]-3′-(3-chloro-4-carbomethoxyphenyl)-pentane

Using a procedure analogous to Example 35C,3′-(4-hydroxy-3-methylphenyl)-3′-[3-chloro-4-carbomethoxyphenyl]pentane,1-chloropinacolone, anhydrous KI, and K2CO3 are reacted in acetonitrileto give the title compound as a clear colorless oil (3.46 g, 90%).

H-NMR (300 mHz, CDCl₃): δ 7.70 (1H, d, J=8.2 Hz), 7.28 (1H, d, J=1.8Hz), 7.07 (1H, dd, J=1.8, J=8.2), 6.858-6.87 (2H, m), 6.50 (1H, d, J=9.2Hz), 4.84 (2H, s), 3.91 (3H, s), 2.23 (3H, s), 2.05 (4H, q, J=7.3 Hz),1.53 (9H, s), 0.61 (6H, t, J=7.3 Hz).

FAB (+) MS m/z [M+H]: 445.2 Calc. m/z 445.2.

IR (CHCl3): 1725 cm⁻¹.

D. Racemic3′-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carbomethoxyoxyphenyl)pentane

Using a procedure analogous to Example 35G,3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-methyl-phenyl]-3′-(3-chloro-4-carbomethoxyphenyl)-pentanewas reduced by NaBH4 to provide the title compound as a colorless oil(2.75 g, 91%).

H-NMR (300 mHz, CDCl₃): δ 7.75 (1H, d, J=8.8 Hz), 7.27 (1H, d, J=1.8Hz), 7.16 (1H, d, J=2.0 Hz), 7.07 (1H, dd, J=1.8 Hz, J=8.8 Hz), 6.94(1H, dd, J=2.0 Hz, J=8.8 Hz), 6.83 (1H, d, J=8.8 Hz), 4.18 (1H, dd,J=2.6 Hz, J=9.0 Hz), 3.92 (3H, s), 3.89 (1H, m), 3.74 (1H, m), 2.60,(1H, broad s), 2.06 (4H, q, J=7.3 Hz), 1.04 (9H, s), 0.63 (6H, t, J=7.3Hz).

FAB (+) MS m/z [M+H]: 447.3; calc. m/z 447.2.

IR(CHCl3): 1733 cm⁻¹.

E. Racemic3′-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane

Using a procedure analogous to Example 35H, racemic3′-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carbomethoxyoxyphenyl)pentanewas saponified by aqueous NaOH in EtOH to form the Na salt correspondingto the desired compound. After removal of the EtOH under reducedpressure, the residue containing the Na salt was dissolved in water andacidified in a manner analogous to the procedure of Example 39I toprovide the title compound as a white solid (1.84 g, 93%).

H-NMR (300 mHz, DMSO): δ 7.69 (1H, d, J=8.0 Hz), 7.10 to 7.20 (2H, m),6.80 to 6.95 (3H, m), 4.78 (1H, d, J=5.6 Hz), 4.02 (1H, dd, J=2.8 Hz,J=10.4 Hz), 3.76 (1H, dd, J=7.0 Hz, J=10.4 Hz), 3.44 (1H, m), 2.10 (3H,s), 2.04 (4H, q, J=7.3 Hz), 0.93 (9H, s), 0.56 (6H, t, J=7.3 Hz).

ES (+) MS m/z 433.2 [M+H], 450.1 [M+NH4], 455.1 [M+Na].

ES (−) MS m/z 431.2 [M−H].

IR(CHCl3): 1701 cm⁻¹.

Example 40 Preparation of racemic3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane

A.3′-(4-hydroxy-3-chlorophenyl)-3′-(3-chloro-4-carbomethoxy-phenyl)pentane

Using a procedure analogous to Example 35D,[E,Z]-3-[3-chloro-4-carbomethoxyphenyl]-3-pentene and o-chlorophenol arereacted (initially at RT overnight, then at 70° C. for 20 h, and finallyat 90° C. overnight) to give the title compound as an oil (886 mg, 58%).

H-NMR (300 mHz, CDCl₃): 6.90 to 7.76 (6H, m), 5.45 (1H, s), 3.93 (3H,s), 2.06 (4H, q, J=7.3 Hz), 0.64 (6H, t, J=7.3 Hz).

ES (+) MS m/z 367.0 [M+H].

IR (CHCl₃): 1726 cm⁻¹.

B.3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-chlorophenyl]-3′-(3-chloro-4-carbomethoxyphenyl)-pentane

Using a procedure analogous to Example 35C,3′-(4-hydroxy-3-chlorophenyl)-3′-(3-chloro-4-carbomethoxy-phenyl)pentane,1-chloropinacolone, anhydrous KI, and K2CO3 are reacted in acetonitrileto give the title compound as a clear, nearly colorless oil (919 mg,89%).

H-NMR (300 mHz, CDCl3): δ 7.72 (1H, d, J=8.2 Hz), 7.26 (1H, m), 7.17(1H, d, J=2.3, 7.06 (1H, dd, J=1.8 Hz, J=8.2 Hz), 6.90 (1H, dd, J=8.7Hz, J=2.3 Hz), 4.91 (2H, s), 3.92 (3H, s), 2.05 (4H, q, J=7.3 Hz), 1.26(9H, s), 0.62 (6H, t, J=7.3 Hz).

ES (+) MS m/z 465.1 [M+H], 482.1 [M+NH4].

C. Racemic3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carbomethoxyphenyl)pentane

Using a procedure analogous to Example 35G,3′-[4-(2-oxo-3,3-trimethylbutoxy)-3-chlorophenyl]-3′-(3-chloro-4-carbomethoxyphenyl)-pentanewas reduced by NaBH4 to provide the title compound as a colorless oil(738 mg, 98%).

H-NMR (300 mHz, CDCl₃): δ 7.89 (1H, d, J=8.8 Hz), 7.13 (1H, d, J=1.78Hz), 7.00 (2H, m), 6.93 (1H, dd, J=2.2 Hz, J=8.8 Hz), 6.80 (1H, d, J=8.8Hz), (4.17 (1H, dd, J=2.6 Hz, J=9.0 Hz), 3.86 (1H, m), 3.85 (3H, s),3.74 (1H, m), 2.60, (1H, d, J=3.0 Hz), 2.06 (4H, q, J=7.3 Hz), 1.01 (9H,s), 0.61 (6H, t, J=7.3 Hz).

ES (+) MS m/z 489.2 (M+Na).

IR (CHCl3): 1717 cm⁻¹.

D. Racemic3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane

Using a procedure analogous to Example 35H, racemic3′-[3-methyl-4-(2-hydroxy-3,3-dimethylbutoxy)phenyl]-3′-(3-chloro-4-carbomethoxy-phenyl)pentanewas saponified by aqueous NaOH in EtOH to form the Na salt correspondingto the desired compound. After removal of the EtOH under reducedpressure, the residue containing the Na salt was dissolved in water andacidified in a manner analogous to the procedure of Example 391 toprovide the title compound as a white solid (517 mg, 94%).

H-NMR (300 mHz, DMSO): δ 7.74 (1H, d, J=8.0 Hz), 7.04 to 7.30 (5H, m),4.88 (1H, d, J=5.6 Hz), 4.14 (1H, dd, J=2.8 Hz, J=10.4 Hz), 3.89 (1H,dd, J=7.0 Hz, J=10.4 Hz), 3.49 (1H, m), 2.04 (4H, q, J=7.3 Hz), 0.95(9H, s), 0.58 (6H, t, J=7.3 Hz).

ES (+) MS m/z 475.2 [M+Na].

IR (CHCl3): 1701 cm⁻¹.

Example 41 and Example 42 Separation of optical isomers of3′-[3-chloro-4-(2-hydroxy-3,3-dimethyl-butoxy)phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane

A racemic mixture3′-[3-chloro-4-(2-hydroxy-3,3-dimethylbutoxy)-phenyl]-3′-(3-chloro-4-carboxyphenyl)pentane.(490 mg) is chromatographed with a ChiralpakAD column to give enantiomer1, Example 41 (192 mg, 39%) and enantiomer 2, Example 42 (185 mg, 38%).

Enantiomer 1, Example 41

HPLC: Chiralpak AD (4.6×250 mm); 3:2 heptane:isopropyl alcohol with 0.1%TFA; 1.0 mL/m (flow rate); rt=7.8 m; 270 nm; ee 99.9% by HPLC.

H-NMR (300 mHz, DMSO): δ 7.74 (1H, d, J=8.0 Hz), 7.04 to 7.30 (5H, m),4.88 (1H, d, J=5.6 Hz), 4.14 (1H, dd, J=2.8 Hz, J=10.4 Hz), 3.89 (1H,dd, J=7.0 Hz, J=10.4 Hz), 3.49 (1H, m), 2.04 (4H, q, J=7.3 Hz), 0.95(9H, s), 0.58 (6H, t, J=7.3 Hz).

ES (+) MS m/z 475.2 [M+Na].

Enantiomer 2, Example 42

HPLC: Chiralpak AD (4.6×250 mm); 3:2 heptane:isopropyl alcohol with0.1%.

TFA; 1.0 mL/m (flow rate); rt=10.6 m; 270 nm; ee 99.5% by HPLC.

H-NMR (300 mHz, DMSO): δ 7.74 (1H, d, J=8.0 Hz), 7.04 to 7.30 (5H, m),4.88 (1H, d, J=5.6 Hz), 4.14 (1H, dd, J=2.8 Hz, J=10.4 Hz), 3.89 (1H,dd, J=7.0 Hz, J=10.4 Hz), 3.49 (1H, m), 2.04 (4H, q, J=7.3 Hz), 0.95(9H, s), 0.58 (6H, t, J=7.3 Hz).

ES (+) MS m/z 475.1 [M+Na].

Example 43 Preparation of racemic1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol

A. 3′-(4-Iodophenyl)-3′-pentanol

To ethyl, p-iodobenzoate (11.04 g, 40 mmol) in diethylether (100 mL) at−20° C. under nitrogen is added 1M ethylmagnesium bromide (91 mL, 91mmol) dropwise with mechanical stirring, and the mixture is allowed tocome to R.T. and stirred over night. The mixture is quenched with satd.sodium bicarbonate and triturated with diethylether six times. Theorganic layers are combined; washed with water; dried over anhydroussodium sulfate; and evaporated under vacuum to give the title compoundas an oil (10.4 g, 90%) which is used as is.

¹H NMR (400 mHz, CDCl₃), δ 7.64 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz,2H), 1.74-1.85 (m, 4H), 0.75 (t, J=7.4 Hz, 6 h).

B. 1-{4-[1-Ethyl-1-(4-iodophenyl)-propyl]}-2-methyl-phenol

To 3′-(4-iodophenyl)-3′-pentanol (10.4 g, 36 mmol) and o-cresol (15.5 g,143 mmol) in methylene chloride (5 mL) is added borontrifluorideetherate (0.96 mL, 7.2 mmol), and the mixture is allowed to stir at roomtemperature overnight. The mixture is quenched with satd. sodiumbicarbonate, and extracted into diethylether. The organic phase iswashed with water; dried over anhydrous sodium sulfate; and evaporatedunder vacuum. The residue is vacuum distilled (0.5 mm) to 80° C. toremove excess o-cresol, and the residue is partitioned betweendiethylether and water. The organic layer is dried over anhydrous sodiumsulfate, and evaporated under vacuum to give the title compound as anoil (13 g, 95%) which is used as is.

¹H NMR (400 mHz, CDCl₃), δ 7.53 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz,2H), 6.84 (s, 1H), 6.83 (d. J=8.9 Hz, 1H), 6.64 (d, J=8.9 Hz, 1H), 4.50(s, 1H), 2.20 (s, 3H), 2.01 (q, J=7.2 Hz, 4H), 0.60 (t, J=7.2 Hz, 6H).

C.1-{4-[1-Ethyl-1-(4-iodophenyl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one

In a procedure analogous to Example 35C,1-{4-[1-Ethyl-1-(4-iodophenyl)-propyl]}-2-methyl-phenol (13 g, 34 mmol)gave the title compound as an oil (13.9 g, 85%) which is used as is.

¹H NMR (400 mHz, CDCl₃), δ 7.53 (d, J=8.4 hz, 2H), 6.90 (d, J=8.4 Hz,2H), 6.87 (s, 1H), 6.86 (d, J=8.8 hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 4.83(s, 2H), 2.23 (s, 3H), 2.01 (q, J=7.2 Hz, 4H), 1.25 (s, 9H).

D.4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzonitrile

To a mixture of1-{4-[1-ethyl-1-(4-iodo-phenyl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one(3.0 g 6.27 mmol) and DMF (30 mL) is added Zn(CN)₂ (0.44 g, 3.76 mmol),Pd₂(dba)₃ (0.29 g, 0.31 mmol), and DPPF (0.42 g, 0.75 mmol). Thesolution is heated at 100° C. overnight, diluted with Et₂O (200 mL),washed with 4:1:4 sat NH₄Cl:Conc. NH₄OH:water (100 mL), water (100 mL),brine (100 mL), dried MgSO₄, filtered and concentrated. The residue ispurified by ISCO (10%-2-% EtOAc gradient) to furnish the title compound(1.1 g, 2.91 mmol, 46%).

¹H NMR (CDCl₃), δ 0.52-0.63 (m, 6H), 1.26 (s, 9H), 2.03-2.10 (m, 4H),2.24 (s, 3H), 4.85 (s, 2H), 6.50 (d, J=9.4 Hz, 1H), 6.82-6.86 (m, 2H),7.27 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.9 Hz, 2H).

LC/MS (m/z): calcd. for C₂₅H₃₁NO₂ (M+H)⁺: 378.6; found: 395.3.

E1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one

To a mixture of4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzonitrile(0.50 g, 1.32 mmol), and DMF (5 mL) is added NaN₃ (0.26 g, 3.95 mmol)and Et₃N.HCl (0.54 g, 3.95 mmol). The slurry is heated at 110° C.overnight. The slurry is diluted with EtOAc (50 mL), washed with 1M HCl(40 mL) water (40 mL), brine (40 mL), dried over MgSO₄, filtered andconcentrated. The residue is purified by ISCO (20%-40% [89% EtOAc: 10%MeOH: 1% AcOH] gradient) to furnish the title compound (0.37 g, 0.88mmol, 66%).

¹H NMR (CDCl₃), δ 0.57-0.62 (m, 6H), 1.27 (s, 9H), 2.02-2.11 (m, 4H),2.17 (s, 3H), 4.87 (s, 2H), 6.50 (d, J=9.4 Hz, 1H), 6.82-6.88 (m, 2H),7.22-7.28 (m, 3H), 7.94 (d, J=7.9 Hz, 2H).

LC/MS (m/z): calcd. for C₂₅H₃₂N₄O₂ (M+H)⁺: 421.7; found: 421.2.

F.1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol

To a mixture of1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one(0.37 g, 0.88 mmol) and EtOH (5 mL) was added NaBH₄ (0.037 g, 0.97 mmol)and the solution stirred for 1 hour. The solids were removed byfiltration and the solution concentrated. The residue was purified byISCO (10-30 [89% EtOAc: 10% MeOH: 1% AcOH] gradient) to furnish thetitle compound (0.32 g, 0.76 mmol, 86%).

¹H NMR (CDCl₃), δ 0.59-0.64 (m, 6H), 1.02 (s, 9H), 2.05-2.12 (m, 4H),2.13 (s, 3H), 3.75 (dd, J=2.8, 8.8 Hz, 1H), 3.89 (t, J=8.8 Hz, 1H), 4.10(dd, J=2.8, 8.8 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H),6.92 (dd, J=2.2, 8.7 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz,2H).

LC/MS (m/z): calcd. for C₂₅H₃₄N₄O₂ (M+H)⁺: 423.7; found: 423.2.

Example 44 and Example 45 Separation of enantiomers of1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol

A racemic mixture of1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol(0.32 g) is chromatographed (CHIRALPAK ADH column, 0.1% TFA, 20%i-PrOH/Hept) to give enantiomer 1, (0.168 g, 0.40 mmol, 45%) andenantiomer 2, (0.150 g, 0.35 mmol, 41%).

Example 44, enantiomer 1

Rt=7.7 m

¹H NMR (CDCl₃), δ 0.57-0.67 (m, 6H), 1.02 (s, 9H), 2.05-2.12 (m, 4H),2.14 (s, 3H), 3.74 (dd, J=2.2, 8.8 Hz, 1H), 3.89 (t, J=8.8 Hz, 1H), 4.10(dd, J=2.2, 8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.86 (s, 1H), 6.93 (d,J=8.8 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.99 (d, J=8.0 Hz, 2H). LC/MS(m/z): calcd. for C₂₅H₃₄N₄O₂ (M+H)⁺: 423.7; found: 423.3.

Example 45, enantiomer 2

Rt=11.6 m

¹H NMR (CDCl₃), δ 0.59-0.66 (m, 6H), 1.01 (s, 9H), 2.05-2.15 (m, 4H),2.16 (s, 3H), 3.71 (dd, J=2.5, 8.7 Hz, 1H), 3.87 (t, J=9.0 Hz, 1H), 4.09(dd, J=2.5, 9.0 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.87 (d, J=1.7 Hz, 1H),6.95 (dd, J=2.2, 8.5 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 8.01 (d, J=8.2 Hz,2H). LC/MS (m/z): calcd. for C₂₅H₃₄N₄O₂ (M+H)⁺: 423.7; found: 423.3.

Example 46 Preparation of epimer 1 of(D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid

A. Preparation of epimer 1 of(D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid methyl ester

Using a procedure analogous to Example 5, isomer 1 of4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid (0.55 g, 1.29 mmol). (D)-alananine methyl ester hydrochloride (198mg, 1.42 mmol), EDCI (276 mg, 1.44 mmol), and 1-hydroxybenzotriazolehydrate (195 mg, 1.44 mmol) furnish the title compound (0.42 g, 0.82mmol, 63%).

¹H NMR (CDCl₃), δ 0.62 (t, J=7.3 Hz, 6H), 0.97 (S, 9H), 1.35 (d, J=6.3Hz, 3H), 1.51 (d, J=7.5 Hz, 3H), 2.06 (q, J=7.3 Hz, 4H), 2.14 (s, 3H),2.43 (s, 3H), 3.18 (bs, 1H), 3.79 (s, 3H), 4.58 (q, J=6.3 Hz, 1H), 4.79(m, 1H), 6.32 (d, J=8.1 Hz, 1H), 6.69 (d, J=8.3 Hz, 1H), 6.84-7.05 (m,4H), 7.30 (d, J=8.3 Hz, 1H).

ES-MS (m/z): calcd. for C₃₁H₄₆NO₅ (M+H)⁺: 511.7; found: 512.3.

B. Preparation of epimer 1 of(D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid

Using a procedure analogous to Example 2, epimer 1 of(D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid methyl ester (0.42 g, 0.82 mmol) and LiOH give the title compound(0.41 g, 0.82 mmol, 100%).

¹H NMR (CDCl₃), δ 0.62 (t, J=7.5 Hz, 6H), 0.97 (S, 9H), 1.36 (d, J=6.2Hz, 3H), 1.57 (d, J=7.0 Hz, 3H), 2.06 (q, J=7.5 Hz, 4H), 2.14 (s, 3H),2.44 (s, 3H), 3.19 (d, J=0.9 Hz, 1H), 4.58 (dq, J=6.2, 0.9 Hz, 1H),4.74-4.82 (m, 1H), 6.28 (d, J=7.0 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H),6.84-7.06 (m, 4H), 7.31 (d, J=7.9 Hz, 1H). ES-MS (m/z): calcd. forC₃₁H₄₆NO₅ (M+H)⁺: 511.7; found: 512.3.).

ES-MS (m/z): calcd for C₃₀H₄₂NO₅ (M−H)⁻: 496.7; found: 496.3.

Example 47 Preparation of epimer 1 of(L)-2-(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid

A. Preparation of epimer 1 of(L)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid methyl ester

Using the procedure analogous to Example 46A, isomer 1 of4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid (0.55 g, 1.29 mmol) and (L)-alananine methyl ester hydrochloride(198 mg, 1.42 mmol) furnish the title compound (0.56 g, 1.09 mmol, 85%).

¹H NMR (CDCl₃), δ 0.62 (t, J=7.2 Hz, 6H), 0.97 (S, 9H), 1.36 (d, J=6.1Hz, 3H), 1.51 (d, J=7.4 Hz, 3H), 2.06 (q, J=7.2 Hz, 4H), 2.15 (s, 3H),2.43 (s, 3H), 3.18 (bs, 1H), 3.79 (s, 3H), 4.58 (dq, J=6.1, 0.9 Hz, 1H),4.79 (m, 1H), 6.32 (d, J=7.3 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.84-7.05(m, 4H), 7.30 (d, J=8.3 Hz, 1H).

ES-MS (m/z): calcd. for C₃₁H₄₆NO₅ (M+H)⁺: 511.7; found: 512.3.

B. Preparation of epimer 1 of(L)-2-(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid

Using a procedure analogous to Example 46B, epimer 1 of(D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid methyl ester (0.56 g, 1.09 mmol) gives the title compound (0.54 g,1.09 mmol, 100%).

¹H NMR (CDCl₃), δ 0.62 (t, J=7.0 Hz, 6H), 0.97 (S, 9H), 1.36 (d, J=6.1Hz, 3H), 1.57 (d, J=7.4 Hz, 3H), 2.06 (q, J=7.0 Hz, 4H), 2.14 (s, 3H),2.44 (s, 3H), 3.19 (d, J=1.3 Hz, 1H), 4.59 (q, J=6.1, Hz, 1H), 4.74-4.82(m, 1H), 6.29 (d, J=7.0 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.84-7.07 (m,4H), 7.31 (d, J=8.4 Hz, 1H).

ES-MS (m/z): calcd for C₃₀H₄₂NO₅ (M−H)⁻: 496.7; found: 496.3.

Example 48 Preparation of epimer 2 of(D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid

A. Preparation of epimer 2 of(D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid methyl ester

Using the procedure analogous to Example 46A, isomer 2 of4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid (0.50 g, 1.17 mmol) and (D)-alananine methyl ester hydrochloride(180 mg, 1.29 mmol) furnish the title compound (0.47 g, 0.92 mmol, 79%).¹H NMR) & ES-MS (m/z): identical to that of Example 47A.

B. Preparation of epimer 2 of(D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid

Using a procedure analogous to Example 46B, from epimer 2 of(D)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid methyl ester (0.47 g, 0.92 mmol) to give the title compound (0.39g, 0.79 mmol, 86%). ¹H NMR & ES-MS: identical to that of Example 47B.

Example 49 Preparation of epimer 2 of(L)-2-(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid

A. Preparation of epimer 2 of(L)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid methyl ester

Using the procedure analogous to Example 46A, isomer 2 of4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid (0.50 g, 1.17 mmol) and (L)-alananine methyl ester hydrochloride(180 mg, 1.29 mmol) furnish the title compound (0.47 g, 0.92 mmol, 79%).¹H NMR) & ES-MS (m/z): identical to that of Example 46A.

B. Preparation of epimer 2 of(L)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid

Using a procedure analogous to Example 24B, epimer 2 of(L)-2-(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoylamino)-propionicacid methyl ester (0.47 g, 0.92 mmol) give the title compound (0.44 g,0.88 mmol, 96%). ¹H NMR & ES-MS: identical to that of Example 46B.

Example 50 Preparation of enantiomer 1 of5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyl)-thiazolidine-2,4-dione

A. Enantiomer 1 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide

To a mixture of enantiomer 1 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid (1.11 g, 2.69 mmol) and DMF (5 mL) is added hydroxylaminehydrochloride (0.29 g, 2.96 mmol), EDCI (0.57 g, 2.96 mmol), HOBt (0.40g, 2.96 mmol), and NEt₃ (1.65 mL, 11.84 mmol). The mixture is stirred atambient temperature overnight, diluted with EtOAc (40 mL), washed with1M HCl (40 mL), water (40 mL), brine (40 mL), dried over MgSO₄, filteredand concentrated. The residue is purified by ISCO (110%-40% EtOAcgradient) to furnish the title compound (1.0 g, 2.19 mmol, 81%).

¹H NMR (CDCl₃), δ 0.57-0.64 (m, 6H), 1.02 (s, 9H), 2.02-2.10 (m, 4H),2.17 (s, 3H), 2.29 (s, 3H), 3.28 (bs, 3H), 3.53 (bs, 1H), 3.71 (dd,J=2.7, 8.8 Hz, 1H), 3.86 (t, J=8.8 Hz, 1H), 4.10 (dd, J=2.7, 8.8 Hz,1H), 6.70 (d, J=8.6 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.94 (dd, J=2.2,8.1 Hz, 1H), 6.97-7.02 (m, 3H), 7.14 (d, J=8.4 Hz, 1H). LC/MS (m/z):calcd. for C₂₈H₄₁NO₄ (M+H)⁺: 456.7; found: 456.2.

B. Enantiomer 1 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde

To a mixture of enantiomer 1 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide(1.0 g, 2.42 mmol) and THF (10 mL) is added 1M in THF LAH (2.5 mL, 2.55mmol) with cooling. THF (5 mL) was added and the solution stirred for 1hour. The solution is diluted with Et₂O (100 mL) and washed with 1M HCl(50 mL). The aqueous phase is extracted with Et₂O (50 mL). The combinedorganic layers are washed with 1M HCl (50 mL), brine (50 mL), dried overMgSO₄, filtered and concentrated to furnish the title compound (0.64 g,1.61 mmol, 67%).

¹H NMR (CDCl₃), δ 0.59-0.66 (m, 6H), 1.02 (s, 9H), 2.05-2.15 (m, 4H),2.18 (s, 3H), 2.62 (s, 3H), 3.71 (dd, J=1.9, 9.1 Hz, 1H), 3.86 (t, J=9.1Hz, 1H), 4.10 (dd, J=1.9, 9.1 Hz, 1H), 6.72 (d, J=8.2 Hz, 1H), 6.87 (s,1H), 6.93 (d, J=8.7 Hz, 1H), 7.06 (s, 1H), 7.17 (d, J=8.2 Hz, 1H) 7.67(dd, J=1.7, 8.0, 1H), 10.20 (s, 1H).

LC/MS (m/z): calcd. for C₂₆H₃₆O₃ (M+H)⁺: 397.7; found: N/A.

C. Enantiomer 1 of5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione

To a mixture of enantiomer 1 of4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde(0.64 g, 1.61 mmol) and toluene (20 mL) is added 90%2,4-thiazolidinedione (0.25 g, 1.94 mmol), and piperidine acetate (0.04g, 0.24 mmol). The solution is heated to a reflux overnight and thewater removed by a Dean-Stark trap. The solution is diluted with EtOAc(60 mL), washed with water (50 mL), saturated NaHCO₃ (50 mL), dried overMgSO₄, filtered and concentrated. Purified by ISCO (20%-50% EtOAcgradient) to furnish the title compound (0.75 g, 1.51 mmol, 94%).

¹H NMR (CDCl₃), δ 0.60-0.67 (m, 6H), 1.03 (s, 9H), 2.04-2.13 (m, 4H),2.19 (s, 3H), 2.42 (s, 3H), 2.50 (d, J=2.0 Hz, 1H), 3.72 (d, J=8.8 Hz,1H), 3.86 (t, J=8.9 Hz, 1H), 4.10 (dd, J=2.7, 9.4 Hz, 1H), 6.72 (d,J=8.1 Hz, 1H), 6.88 (d, J=1.7 Hz, 1H), 6.94 (dd, J=2.3, 8.7 Hz, 1H),7.08 (s, 1H), 7.11 (dd, J=1.8, 8.4 Hz, 1H), 7.33 (d, J=8.4, 1H), 8.06(s, 1H), 8.97 (bs, 1H).

LC/MS (m/z): calcd. for C₂₉H₃₇NO₄S (M+H)⁺: 494.5; found: 494.2.

D. Enantiomer 1 of5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyl)-thiazolidine-2,4-dione

To a mixture of enantiomer 1 of5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione(0.35 g, 0.71 mmol) and MeOH (10 mL) is added Mg (0.17 g, 7.1 mmol). Thesolution is heated at a reflux for 4 hours. The solution is filteredthru Celite®, rinsed with MeOH (2 mL), and the solution concentrated.The residue is purified by ISCO (15%-30% EtOAc gradient) to furnish thetitle compound (0.13 g, 0.26 mmol, 37%).

¹H NMR (CDCl₃), δ 0.57-0.65 (m, 6H), 1.02 (s, 9H), 2.01-2.10 (m, 4H),2.19 (s, 3H), 2.31 (s, 3H), 2.50 (d, J=2.6 Hz, 1H), 2.97-3.06 (m, 1H),3.65 (dd, J=3.8, 14.5 Hz, 1H), 3.69-3.75 (m, 1H), 3.87 (t, J=8.8 Hz,1H), 4.10 (dd, J=2.7, 9.3 Hz, 1H), 4.52 (dd, J=3.8, 11.2 Hz, 1H), 6.70(dd, J=2.3, 8.5 Hz, 1H), 6.87-7.04 (m, 5H), 8.56 (bs, 1H).

LC/MS (m/z): calcd. for C₂₉H₃₉NO₄S (M+H)⁺: 496.6; found: 496.2.

Example 51 Preparation of enantiomer 2 of5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyl)-thiazolidine-2,4-dione

A. Enantiomer 2 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide

To mixture of enantiomer 2 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid (0.70 g, 1.70 mmol) and DMF (5 mL) is added hydroxylaminehydrochloride (0.18 g, 1.87 mmol), EDCI (0.33 g, 1.87 mmol), HOBt (0.23g, 1.87 mmol), and NEt₃ (0.95 mL, 6.79 mmol). The mixture is stirred atambient temperature overnight, diluted with EtOAc (40 mL), washed with1M HCl (40 mL), water (40 mL), brine (40 mL), dried over MgSO₄, filteredand concentrated to furnish the title compound (0.76 g, 2.19 mmol, 81%).

¹H NMR (CDCl₃), δ 0.57-0.64 (m, 6H), 1.02 (s, 9H), 2.01-2.10 (m, 4H),2.17 (s, 3H), 2.28 (s, 3H), 3.28 (bs, 3H), 3.54 (bs, 1H), 3.71 (dd,J=2.6, 8.8 Hz, 1H), 3.86 (t, J=8.8 Hz, 1H), 4.10 (dd, J=2.6, 8.8 Hz,1H), 6.70 (d, J=8.3 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H), 6.94 (dd, J=2.2,8.6 Hz, 1H), 6.97-7.02 (m, 3H), 7.13 (d, J=8.3 Hz, 1H). LC/MS (m/z):calcd. for C₂₈H₄₁NO₄ (M+H)⁺: 456.7; found: 456.3.

B. Enantiomer 2 of4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde

To a mixture of enantiomer 2 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide(0.76 g, 1.75 mmol) and THF (20 mL) is added 1M LAH in THF (1.75 mL,1.75 mmol) with cooling, and the solution stirred for 1 hour. Thesolution is diluted with Et₂O (100 mL) and washed with 1M HCl (50 mL).The aqueous phase is extracted with Et₂O (50 mL). The combined organiclayers are washed with 1M HCl (50 mL), brine (50 mL), dried over MgSO₄,filtered and concentrated to furnish the title compound (0.48 g, 1.21mmol, 73%).

¹H NMR (CDCl₃), δ 0.60-0.65 (m, 6H), 1.02 (s, 9H), 2.07-2.14 (m, 4H),2.18 (s, 3H), 2.62 (s, 3H), 3.58-3.74 (m, 1H), 3.87 (t, J=8.9 Hz, 1H),4.10 (dd, J=2.6, 9.2 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 6.87 (d, J=2.5,8.6, 1H), 7.06 (s, 1H), 7.17 (dd, J=1.8, 8.2 Hz, 1H), 7.67 (d, J=8.4,1H), 10.20 (s, 1H).

LC/MS (m/z): calcd. for C₂₆H₃₆O₃ (M+H)⁺: 397.7; found: 397.3.

C. Enantiomer 2 of5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione

To a mixture of enantiomer 2 of4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde(048 g, 1.21 mmol) and toluene (15 mL) is added 90%2,4-thiazolidinedione (0.19 g, 1.45 mmol), and piperidine acetate (0.03g, 0.18 mmol). The solution is heated to a reflux overnight and thewater removed by a Dean-Stark trap. The solution is diluted with EtOAc(60 mL), washed with water (50 mL), brine (50 mL), dried over MgSO₄,filtered and concentrated. Purified by ISCO (20% 40% EtOAc gradient) tofurnish the title compound (0.50 g, 1.00 mmol, 83%).

¹H NMR (CDCl₃), δ 0.60-0.67 (m, 6H), 1.03 (s, 9H), 2.05-2.12 (m, 4H),2.19 (s, 3H), 2.42 (s, 3H), 2.51 (d, J=2.5 Hz, 1H), 3.70-3.75 (m, 1H),3.88 (t, J=8.8 Hz, 1H), 4.10 (dd, J=2.7, 9.2 Hz, 1H), 6.72 (d, J=8.3 Hz,1H), 6.88 (d, J=1.8 Hz, 1H), 6.94 (dd, J=2.2, 8.6 Hz, 1H), 7.08 (s, 1H),7.11 (dd, J=1.8, 8.0 Hz, 1H), 7.33 (d, J=8.0, 1H), 8.06 (s, 1H), 9.02(bs, 1H).

LC/MS (m/z): calcd. for C₂₉H₃₇NO₄S (M+H)⁺: 494.5; found: 494.2.

D. Enantiomer 2 of5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzyl)-thiazolidine-2,4-dione

To a mixture of enantiomer 2 of5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione(example Rupp-7) (0.25 g, 0.50 mmol) and MeOH (10 mL) is added Mg (0.12g, 5.04 mmol). The solution is heated at a reflux for 4 hours. Thesolution is filtered thru celite® rinsed with MeOH (2 mL), and thesolution concentrated. The residue is purified by ISCO (15%-30% EtOAcgradient) to furnish the title compound (0.084 g, 0.17 mmol, 34%).

¹H NMR (CDCl₃), δ 0.56-0.63 (m, 6H), 1.02 (s, 9H), 2.00-2.10 (m, 4H),2.18 (s, 3H), 2.31 (s, 3H), 2.51 (d, J=2.1 Hz, 1H), 2.97-3.06 (m, 1H),3.65 (dd, J=3.9, 14.7 Hz, 1H), 3.69-3.75 (m, 1H), 3.86 (t, J=8.9 Hz,1H), 4.09 (dd, J=2.7, 9.4 Hz, 1H), 4.52 (dd, J=3.8, 11.2 Hz, 1H), 6.70(d, J=8.5 Hz, 1H), 6.86-7.03 (m, 5H), 8.56 (bs, 1H). LC/MS (m/z): calcd.for C₂₉H₃₉NO₄S (M+H)⁺: 496.6; found: 496.2.

Example 52 and 53 Enantiomer 1 and 2 of[(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid

A. Racemic[(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid methyl ester

Using a procedure analogous to Example 46A, from racemic4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoicacid (1.46 g, 3.43 mmol) and sascoine methyl ester hydrochloride (0.52g, 3.76 mmol) to give the title compound (1.74 g, 3.40 mmol, 99%).

¹H NMR (CDCl₃), δ 0.58-0.65 (m, 6H), 0.97 (s, 6H), 1.02 (s, 3H), 1.33(d, J=6.2 Hz, 1H), 1.36 (d, J=6.2 Hz, 2H), 2.00-2.10 (m, 4H), 2.14 (s,3H), 2.25 (s, 1H), 2.33 (s, 2H), 2.57 (d, J=9.6 Hz, 0.33H), 2.58 (d,J=9.6 Hz, 0.66H), 2.89 (s, 3H), 3.18 (dd, J=9.6, 1.3 Hz, 1H), 3.69 (s,1H), 3.79 (s, 2H), 3.91 (s, 0.66H), 4.32 (bs, 1.34H), 4.59 (dq, J=6.2,1.3 Hz, 1H), 6.69 (d, J=8.3 Hz, 1H), 6.84-7.11 (m, 5H).

ES-MS (m/z): calcd for C₃₁H₄₅NO₅ (M+H)⁺: 512.7; found: 512.3.

B. Separation of enantiomers of[(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid methyl ester

A racemic mixture of[(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid methyl ester (1.73 g), is chromatographed (HPLC: ChiralPak AD, 0.1%TFA in iPrOH:Hept=5:95) to give enantiomer 1 (0.636 g, 38%, rt=21.8 m)and enantiomer 2 (0.72 g, 42%, rt=26.7 m).

(Enantiomer 1)

HPLC: ChiralPak AD, 0.1% TFA in iPrOH:Hept=5:95; 0.6 mL/m (flow rate);rt=21.8 m; @ 240 nm;

NMR & LC/MS: equivalent to the racemate.

(Enantiomer 2)

HPLC: ChiralPak AD, 0.1% TFA in iPrOH:Hept=5:95; 0.60 mL/m (flow rate);rt=26.7 m; @ 240 nm;

NMR & LC/MS: equivalent to the racemate.

C. Enantiomer 1 of[(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid

Using a procedure analogous to Example 46B, enantiomer 1 of[(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid methyl ester (0.63 g, 1.24 μmmol) gives the title compound (0.58 g,1.16 mmol, 93%).

¹H NMR (CDCl₃), δ 0.58-0.65 (m, 6H), 0.98 (s, 9H), 1.36 (d, J=6.2 Hz,3H), 2.06 (q, J=7.1 Hz, 4H), 2.14 (s, 3H), 2.25 (s, 0.9H), 2.31 (s,2.1H), 2.93 (s, 3H), 3.16 (bs, 1H), 3.18 (d, J=1.3 Hz, 1H), 3.95 (s,1H), 4.35 (s, 1H), 4.59 (q, J=6.2 Hz, 1H), 6.68-7.11 (m, 6H).

ES-MS (m/z): calcd for C₃₀H₄₂NO₅ (M−H)⁻: 496.7; found: 496.3.

D. Enantiomer 2 of[(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid

Using a procedure analogous to Example 46B, enantiomer 2 of[(4-{1-ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid methyl ester (0.72 g, 1.41 mmol) gives the title compound (0.64 g,1.28 mmol, 91%). ¹H NMR & ES-MS (m/z): identical to enantiomer 1 of[(4-{1-Ethyl-1-[4-(2-hydroxy-1,3,3-trimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoyl)-methyl-amino]-aceticacid.

Example 54 Preparation of3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane

A.3′-[4-benzyloxy-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentane

Using a procedure analogous to Example 1E,3′-[4-benzyloxy-3-methylphenyl]-3′-[4-trifluoromethanesulfonyloxy-3-methylphenyl]pentanegives the title compound (30 g, 77%).

¹H NMR 300 MHz (DMSO-d₆): δ 0.54 (t, J=6.9 Hz, 6H), 2.05 (q, J=6.9 Hz,4H), 2.12 (s, 3H), 2.47 (s, 3H), 3.78 (s, 3H), 5.06 (s, 2H), 6.91 (m,3H), 7.05 (d, J=8.41 Hz, 1H), 7.11 (s, 1H), 7.29-7.47 (m, 5H), 7.72 (d,J=8.05, 1H).

B.3′-[4-benzyloxy-3-methylphenyl]-3′-[4-hydroxymethyl-3-methylphenyl]pentane

Using a procedure analogous to Example 13B,3′-[4-benzyloxy-3-methylphenyl]-3′-[4-methoxycarbonyl-3-methylphenyl]pentanegives the title compound (6.0 g, quant).

¹H NMR 400 MHz (DMSO-d₆): δ 0.54 (t, J=7.2 Hz, 6H), 2.02 (q, J=7.2 Hz,4H), 2.12 (s, 3H), 2.17 (s, 3H), 4.42 (d, J=6.0 Hz, 2H), 4.94 (t, J=5.6Hz, 1H), 5.05 (s, 2H), 6.87-6.94 (m, 5H), 7.19 (d, J=8.0 Hz, 1H), 7.31(d, J=7.6, 1H), 7.38 (t, J=7.2 Hz, 2H), 7.44 (d, J=7.2 Hz, 2H).

High Res. FAB-MS: 388.2397; calc. for C₂₇H₃₂O₂: 388.2402.

C.3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-benzyloxy-3-methylphenyl]pentane

To a 0° C. mixture of3′-[4-benzyloxy-3-methylphenyl]-3′-[4-hydroxymethyl-3-methylphenyl]pentane(6.0 g, 15.4 mmol) and Et₂O (40 ml) is added PBr₃ (1.6 ml, 17.0 mmol).The reaction is stirred for 2 h and allowed to warm to RT. The reactionis diluted with Et₂O, washed with minimal amount of water, brine, Na₂SO₄dried, concentrated, and azeotrope to dryness with toluene. Theresulting residue is dissolved in THF (4 ml) and cooled to −78° C. toafford the bromide/THF solution. In a separate flask is charged with 1MLiHMDS (31 ml, 30.8 mmol), cooled to −78 C, and added pinacolone (3.9ml, 30.8 mmol). The reaction is stirred for 1.5 h, warmed to −55 C andtransferred (via syringe) to the −78° C. solution of bromide/THF. Thereaction is allowed to warm to RT and stirred for 16 h. The reaction isdiluted with Et2O and washed with 1N HCl. The organic layer is Na2SO4dried and chromatographed (70% CHCl3/Hex) to give the title compound(5.2 g, 71%).

¹H NMR 400 MHz (DMSO-d₆): δ 0.48 (t, J=7.6 Hz, 6H), 0.97 (s, 9H), 1.93(q, J=7.2 Hz, 4H), 2.05 (s, 3H), 2.13 (s, 3H), 2.60 (t, J=8.0 Hz, 2H),2.69 (t, J=8.4 Hz, 2H), 4.98 (d, J=4.4 Hz, 2H), 6.77-6.84 (m, 5H), 6.90(d, J=8.0 Hz, 1H), 7.24-7.26 (m, 1H), 7.32 (t, J=7.2 Hz, 2H), 7.38 (d,J=7.2 Hz, 2H).

D.3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-hydroxy-3-methylphenyl]pentane

Using a procedure analogous to Example 6D,3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-benzyloxy-3-methylphenyl]pentanegives the title compound (3.1 g, 74%).

¹H NMR 400 MHz (DMSO-d₆): δ 0.51 (t, J=6.8 Hz, 6H), 1.03 (s, 9H), 1.96(q, J=7.2 Hz, 4H), 2.03 (s, 3H), 2.19 (s, 3H), 2.66 (t, J=6.4 Hz, 2H),2.74 (t, J=6.4 Hz, 2H), 6.61 (d, J=8.0 Hz, 1H), 6.73 (dd, J=2.0 Hz,J=8.0 Hz, 2H), 6.83-6.86 (m, 2H), 6.95 (d, J=8.0 Hz, 1H), 8.97 (s, J=8.0Hz, 1H).

E.3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-(trifluoromethylsulfonyloxy)-3-methylphenyl]pentane

Using a procedure analogous to Example 1C,3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-hydroxy-3-methylphenyl]pentanegives the title compound (4.2 g, quant).

¹H NMR 400 MHz (DMSO-d₆): δ 0.53 (t, J=7.2 Hz, 6H), 1.03 (s, 9H), 2.05(q, J=7.2 Hz, 4H), 2.21 (s, 3H), 2.27 (s, 3H), 2.66 (t, J=8.4 Hz, 2H),2.74 (t, J=8.0 Hz, 2H), 6.84 (dd, J=1.6 Hz, J=6.4 Hz, 1H), 6.91 (s, 1H),7.00 (d, J=7.6 Hz, 1H), 7.07 (dd, J=2.0 Hz, J=6.4 Hz, 1H), 7.21-7.24 (m,2H).

ES-MS: 530.25 (M+NH4).

F.3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-(methoxycarboxyl)-3-methylphenyl]pentane

Using a procedure analogous to Example 1E,3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-(trifluoromethylsulfonyloxy)-3-methylphenyl]pentanegives the title compound as a white foam (2.1 g, 67%).

¹H NMR 400 MHz (DMSO-d₆): δ 0.53 (t, J=7.2 Hz, 6H), 1.03 (s, 9H), 2.07(q, J=7.2 Hz, 4H), 2.20 (s, 3H), 2.46 (s, 3H), 2.69 (t, J=7.6 Hz, 2H),2.75 (t, J=6.4 Hz, 2H), 3.78 (s, 3H), 6.84 (d, J=8.4 Hz, 1H), 6.88 (s,1H), 6.98 (d, J=8.0 Hz, 1H), 7.03 (dd, J=1.6 Hz, J=6.8 Hz, 1H), 7.08 (s,1H), 7.70 (d, J=8.4 Hz, 1H).

High Res ES (+) MS m/z: 440.3167; calc. for C₂₈H₃₈O₃+NH₄: 440.3165.

G.3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane

Using a procedure analogous to Example 2,3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-(methoxycarboxyl)-3-methylphenyl]pentanegives the title compound as a white foam (1.5 g, 97%).

¹H NMR 300 MHz (DMSO-d₆): δ 0.54 (t, J=7.0 Hz, 6H), 1.03 (s, 9H), 2.07(q, J=6.6 Hz, 4H), 2.20 (s, 3H), 2.46 (s, 3H), 2.68 (d, J=7.0 Hz, 2H),2.73 (d, J=5.9, 2H), 6.85-6.90 (m, 2H), 6.99-7.06 (m, 3H), 7.72 (d,J=8.4 Hz, 1H).

High Res ES (+) MS m/z: 426.3003; calc. for C₂₇H₃₆O₃+NH₄: 426.3008.

Example 55 Preparation of racemic3′-[4-(3-hydroxy-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentane

Using a procedure analogous to Example 1D,3′-[4-(3-oxo-4,4-dimethylpentyl)-3-methylphenyl]-3′-[4-carboxyl-3-methylphenyl]pentanegives the title compound as a white foam (1.5 g, quant).

¹H NMR 300 MHz (DMSO-d₆): δ 0.54 (t, J=7.3 Hz, 6H), 0.80 (s, 9H),1.30-1.36 (m, 1H), 1.58-1.64 (m, 1H), 2.07 (q, J=6.9 Hz, 4H), 2.20 (s,3H), 2.47 (s, 3H), 2.74-2.82 (m, 1H), 2.99-3.04 (m, 1H), 4.41 (d, J=6.2,1H), 6.85-6.89 (m, 2H), 7.02-7.08 (m, 3H), 7.72 (d, J=8.0 Hz, 1H),

High Res ES (+) MS m/z: 428.3145; calc. for C₂₇H₃O₃+NH₄: 428.3165.

Compounds of the Invention—Salts Stereoisomers & Prodrugs:

Salts of the compounds represented by formulae (I) are an additionalaspect of the invention. The skilled artisan will also appreciate thatthe family of compounds of formulae I include acidic and basic membersand that the present invention includes pharmaceutically acceptablesalts thereof.

In those instances where the compounds of the invention possess acidicor basic functional groups various salts may be formed which are morewater soluble and physiologically suitable than the parent compound.Representative pharmaceutically acceptable salts, include but are notlimited to, the alkali and alkaline earth salts such as lithium, sodium,potassium, ammonium, calcium, magnesium, aluminum, zinc, and the like.Salts are conveniently prepared from the free acid by treating the acidin solution with a base or by exposing the acid to an ion exchangeresin. For example, a carboxylic acid substituent on the compound ofFormula I may be selected as —CO₂H and salts may be formed by reactionwith appropriate bases (e.g., NaOH, KOH) to yield the correspondingsodium and potassium salt.

Included within the definition of pharmaceutically acceptable salts arethe relatively non-toxic, inorganic and organic base addition salts ofcompounds of the present invention, for example, ammonium, quaternaryammonium, and amine cations, derived from nitrogenous bases ofsufficient basicity to form salts with the compounds of this invention(see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar.Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound ofthe invention may be reacted with suitable organic or inorganic acids toform salts such as acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride,choline, clavulanate, citrate, chloride, chloroprocaine, choline,diethanolamine, dihydrochloride, diphosphate, edetate, edisylate,estolate, esylate, ethylenediamine, fluoride, fumarate, gluceptate,gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine,bromide, chloride, hydrobromide, hydrochloride, hydroxynaphthoate,iodide, isothionate, lactate, lactobionate, laurate, malate, maleate,malseate, mandelate, meglumine, mesylate, mesviate, methylbromide,methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate,oxalate, palmitate, pamoate, pantothenate, phosphate, polygalacturonate,procane, salicylate, stearate, subacetate, succinate, sulfate, tannate,tartrate, teoclate, tosylate, trifluoroacetate, trifluoromethanesulfonate, and valerate.

Certain compounds of the invention may possess one or more chiralcenters and may thus exist in optically active forms. Likewise, when thecompounds contain an alkenyl or alkenylene group there exists thepossibility of cis- and trans-isomeric forms of the compounds. The R-and S-isomers and mixtures thereof, including racemic mixtures as wellas mixtures of cis- and trans-isomers, are contemplated by thisinvention. Additional asymmetric carbon atoms can be present in asubstituent group such as an alkyl group. All such isomers as well asthe mixtures thereof are intended to be included in the invention. If aparticular stereoisomer is desired, it can be prepared by methods wellknown in the art by using stereospecific reactions with startingmaterials which contain the asymmetric centers and are already resolvedor, alternatively by methods which lead to mixtures of the stereoisomersand subsequent resolution by known methods. For example, a chiral columnmay be used such as those sold by Daicel Chemical Industries identifiedby the trademarks:

CHIRALPAK AD, CHIRALPAK AS, CHIRALPAK OD, CHIRALPAK OJ, CHIRALPAK OA,CHIRALPAK OB, CHIRALPAK OC, CHIRALPAK OF, CHIRALPAK OG, CHIRALPAK OK,and CHIRALPAK CA-1.

By another conventional method, a racemic mixture may be reacted with asingle enantiomer of some other compound. This changes the racemic forminto a mixture of diastereomers. These diastereomers, because they havedifferent melting points, different boiling points, and differentsolubilities can be separated by conventional means, such ascrystallization.

Compounds of the Invention—Salts, Stereoisomers, & Prodrugs:

Salts of the compounds represented by formulae (I) are an additionalaspect of the invention. The skilled artisan will also appreciate thatthe family of compounds of formulae I include acidic and basic membersand that the present invention includes pharmaceutically acceptablesalts thereof.

In those instances where the compounds of the invention possess acidicor basic functional groups various salts may be formed which are morewater soluble and physiologically suitable than the parent compound.Representative pharmaceutically acceptable salts, include but are notlimited to, the alkali and alkaline earth salts such as lithium, sodium,potassium, ammonium, calcium, magnesium, aluminum, zinc, and the like.Salts are conveniently prepared from the free acid by treating the acidin solution with a base or by exposing the acid to an ion exchangeresin. For example, a carboxylic acid substituent on the compound ofFormula I may be selected as —CO₂H and salts may be formed by reactionwith appropriate bases (e.g., NaOH, KOH) to yield the correspondingsodium and potassium salt.

Included within the definition of pharmaceutically acceptable salts arethe relatively non-toxic, inorganic and organic base addition salts ofcompounds of the present invention, for example, ammonium, quaternaryammonium, and amine cations, derived from nitrogenous bases ofsufficient basicity to form salts with the compounds of this invention(see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar.Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound ofthe invention may be reacted with suitable organic or inorganic acids toform salts such as acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride,choline, clavulanate, citrate, chloride, chloroprocaine, choline,diethanolamine, dihydrochloride, diphosphate, edetate, edisylate,estolate, esylate, ethylenediamine, fluoride, fumarate, gluceptate,gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine,bromide, chloride, hydrobromide, hydrochloride, hydroxynaphthoate,iodide, isothionate, lactate, lactobionate, laurate, malate, maleate,malseate, mandelate, meglumine, mesylate, mesviate, methylbromide,methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate,oxalate, palmitate, pamoate, pantothenate, phosphate, polygalacturonate,procane, salicylate, stearate, subacetate, succinate, sulfate, tannate,tartrate, teoclate, tosylate, trifluoroacetate, trifluoromethanesulfonate, and valerate.

Certain compounds of the invention may possess one or more chiralcenters and may thus exist in optically active forms. Likewise, when thecompounds contain an alkenyl or alkenylene group there exists thepossibility of cis- and trans-isomeric forms of the compounds. The R-and S-isomers and mixtures thereof, including racemic mixtures as wellas mixtures of cis- and trans-isomers, are contemplated by thisinvention. Additional asymmetric carbon atoms can be present in asubstituent group such as an alkyl group. All such isomers as well asthe mixtures thereof are intended to be included in the invention. If aparticular stereoisomer is desired, it can be prepared by methods wellknown in the art by using stereospecific reactions with startingmaterials which contain the asymmetric centers and are already resolvedor, alternatively by methods which lead to mixtures of the stereoisomersand subsequent resolution by known methods. For example, a chiral columnmay be used such as those sold by Daicel Chemical Industries identifiedby the trademarks:

CHIRALPAK AD, CHIRALPAK AS, CHIRALPAK OD, CHIRALPAK OJ, CHIRALPAK OA,CHIRALPAK OB, CHIRALPAK OC, CHIRALPAK OF, CHIRALPAK OG, CHIRALPAK OK,and CHIRALPAK CA-1.

By another conventional method, a racemic mixture may be reacted with asingle enantiomer of some other compound. This changes the racemic forminto a mixture of diastereomers. These diastereomers, because they havedifferent melting points, different boiling points, and differentsolubilities can be separated by conventional means, such ascrystallization.

The present invention is also embodied in mixtures of compounds offormulae I.

Prodrugs are derivatives of the compounds of the invention which havechemically or metabolically cleavable groups and become by solvolysis orunder physiological conditions the compounds of the invention which arepharmaceutically active in vivo.

Derivatives of the compounds of this invention have activity in boththeir acid and base derivative forms, but the acid derivative form oftenoffers advantages of solubility, tissue compatibility, or delayedrelease in a mammalian organism (see, Bundgard, H., Design of Prodrugs,pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acidderivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acidic compound witha suitable alcohol, or amides prepared by reaction of the parent acidcompound with a suitable amine. Simple aliphatic or aromatic estersderived from acidic groups pendent on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy) alkyl esters or((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters to useas prodrugs are; methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,tert-butyl, morpholinoethyl, and N,N-diethylglycolamido.

N,N-diethylglycolamido ester prodrugs may be prepared by reaction of thesodium salt of a compound of Formula (I) (in a medium such asdimethylformamide) with 2-chloro-N,N-diethylacetamide (available fromAldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).

Morpholinylethyl ester prodrugs may be prepared by reaction of thesodium salt of a compound of Formula (I) (in a medium such asdimethylformamide) 4-(2-chloroethyl)morpholine hydrochloride (availablefrom Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C5,220-3).

Morpholinylethyl ester prodrugs may be prepared by reaction of thesodium salt of a compound of Formula I (in a medium such asdimethylformamide) 4-(2-chloroethyl)morpholine hydrochloride (availablefrom Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C5,220-3). Theprodrugs, for example, may be prepared by reaction of the sodium saltfor a compound of Formula I with;

and sodium iodide to provide the ester prodrug pendent group

Also, lower alkyl (viz., C₁-C₈) ester prodrugs may be prepared byconventional means such as reacting the sodium or potassium salt(derived by forming the salt of any acidic compound of the invention,viz., reaction of a base such as KOH with an acidic group such as —CO₂H)of a compound of Formula I with an alkyl iodide such as methyl iodide,ethyl iodide, n-propyl iodide, isopropyl iodide. Typical ester prodrugsubstituents are

Pharmaceutical Formulations Containing the Novel Compounds of theInvention:

Pharmaceutical formulations of the invention are prepared by combining(e.g., mixing) a therapeutically effective amount of the compound of theinvention (compounds of Formula I) together with a pharmaceuticallyacceptable carrier or diluent. The present pharmaceutical formulationsare prepared by known procedures using well-known and readily availableingredients.

In making the compositions of the present invention, the compounds ofFormula I will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, or can be in the form of tablets, pills, powders, lozenges,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), or ointment, containing, for example, up to 10%by weight of the compound. The compounds of the present invention arepreferably formulated prior to administration.

The compounds of the invention may also be delivered by suitableformulations contained in a transderm patch. Alternatively, thecompounds of the invention may be delived to a patient by sublingualadministration.

For the pharmaceutical formulations any suitable carrier known in theart can be used. In such a formulation, the carrier may be a solid,liquid, or mixture of a solid and a liquid. Solid form formulationsinclude powders, tablets and capsules. A solid carrier can be one ormore substances which may also act as flavoring agents, lubricants,solubilisers, suspending agents, binders, tablet disintegrating agentsand encapsulating material.

Tablets for oral administration may contain suitable excipients such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate,together with disintegrating agents, such as maize, starch, or alginicacid, and/or binding agents, for example, gelatin or acacia, andlubricating agents such as magnesium stearate, stearic acid, or talc.

In powders the carrier is a finely divided solid which is in admixturewith the finely divided Active ingredient. In tablets the compound ofFormula I is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from about 1 toabout 99 weight percent of the compound which is the novel compound ofthis invention. Suitable solid carriers are magnesium carbonate,magnesium stearate, talc, sugar lactose, pectin, dextrin, starch,gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose,low melting waxes, and cocoa butter.

Sterile liquid form formulations include suspensions, emulsions, syrupsand elixirs.

The compounds of the invention may be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent or a mixture of both. The compounds can often bedissolved in a suitable organic solvent, for instance aqueous propyleneglycol. Other compositions can be made by dispersing the finely dividedcompounds of the invention in aqueous starch or sodium carboxymethylcellulose solution or in a suitable oil.

Methods of Using the Compounds of the Invention:

Generic disease states benefited by treatment with the compounds ofFormula I include, but are not limited to:

-   -   disease states characterized by abnormal calcium regulation    -   disease states characterized by abnormal cell proliferation    -   disease states characterized by abnormal cell differentiation    -   disease states characterized by abnormal immune response    -   disease states characterized by abnormal dermatological        conditions    -   disease states characterized by neurodegenerative condition    -   disease states characterized by inflammation    -   disease states characterized by vitamin D sensitivity    -   disease states characterized by hyperproliferative disorders.        Specific disease states benefited by treatment of the compounds        of Formula I and II include, but are not limited to:    -   Acne    -   Actinic keratosis    -   Alopecia    -   Alzheimer's disease    -   Bone maintenance in zero gravity    -   Bone fracture healing    -   Breast cancer    -   Chemoprovention of Cancer    -   Crohn's disease    -   Colon cancer    -   Type I diabetes    -   Host-graft rejection    -   Hypercalcemia    -   Type II diabetes    -   Leukemia    -   Multiple sclerosis    -   Myelodysplastic syndrome    -   Insufficient sebum secretion    -   Osteomalacia    -   Osteoporosis    -   Insufficient dermal firmness    -   Insufficient dermal hydration    -   Psoriatic arthritis    -   Prostate cancer    -   Psoriasis    -   Renal osteodystrophy    -   Rheumatoid arthritis    -   Scleroderma    -   Skin cancer    -   Systemic lupus erythematosus    -   Skin cell protection from Mustard vesicants    -   Ulcerative colitis    -   Vitiligo    -   Wrinkles

Particularly preferred is the treatment of psoriasis and osteoporosis byadministration to a mammal (including a human) of a therapeuticallyeffective amount of compounds of Formulae I. By “pharmaceuticallyeffective amount” it is meant that quantity of pharmaceutical agentcorresponding to formulae I which prevents, removes or reduces thedeleterious effects of a disease state in mammals, including humans.

The specific dose of a compound administered according to this inventionto obtain therapeutic or prophylactic effects will, of course, bedetermined by the particular circumstances surrounding the case,including, for example, the compound administered, the route ofadministration and the condition being treated. Typical daily doses willcontain a pharmaceutically effective amount typically in the range offrom about 0.0001 mg/kg/day to about 50 mg/kg/day of body weight of anactive compound of this invention. Preferably the dose of compounds ofthe invention will be from 0.0001 to 5 mg/kg/day of body weight.

Preferably compounds of the invention (e.g., per Formula I) orpharmaceutical formulations containing these compounds are in unitdosage form for administration to a mammal. The unit dosage form can bea capsule or tablet itself, or the appropriate number of any of these.The quantity of Active ingredient in a unit dose of composition may bevaried or adjusted from about 0.0001 to about 1000 milligrams or moreaccording to the particular treatment involved. It may be appreciatedthat it is necessary to make routine variations to the dosage dependingon the age and condition of the patient. Dosage will also depend on theroute of administration. The compounds of the invention may beadministered by a variety of routes including oral, aerosol, rectal,transdermal, sublingual, subcutaneous, intravenous, intramuscular, andintranasal. Particularly preferred is the treatment of psoriasis with anointment type formulation containing the compounds of the invention. Theointment formulation may be applied as needed, typically from one to 6times daily.

Treatment of psoriasis is preferably done with topical application by aformulation in the form of a cream, oil, emulsion, paste or ointmentcontaining a therapeutically effective amount of a compound defined byFormula (I), and in particular those compounds set out in Tables 1 or 2or those compounds identified as “AA” to “BQ”, supra. The formulationfor topical treatment contains from 0.5 to 0.00005 weight percent,preferably from 0.05 to 0.0005 weight percent, and most preferably from0.025 to 0.001 of a compound defined by formula (I).

For example, two semisolid topical preparations useful as vehicles forVDR modulators in treatment and prevention of psoriasis are as follows:

Polyethylene Glycol Ointment USP (p. 2495)

Prepare Polyethylene Glycol Ointment as follows:

Polyethylene Glycol 3350 400 g. Polyethylene Glycol 400 600 g. To make1000 g. 

-   -   Heat the two ingredients on a water bath to 65 C. Allow to cool,        and stir until congealed. If a firmer preparation is desired,        replace up to 100 g of the polyethylene glycol 400 with an equal        amount of polyethylene glycol 3350.

Hydrophilic Ointment USP (p. 1216)

Prepare Hydrophilic Ointment as follows:

Methylparaben 0.25 g.  Propylparaben 0.15 g.  Sodium Lauryl Sulfate  10g. Propylene Glycol 120 g. Stearyl Alcohol 250 g. White Petrolatum 250g. Purified Water 370 g. To make about 1000 g. 

The Stearyl Alcohol and White Petrolatum are melted on a steam bath, andwarmed to about 75 C. The other ingredients, previously dissolved in thewater are added, warmed to 75 C, and the mixture stirred until itcongeals.

For each of the above formulations the compound of formula (I) is addedduring the heating step in an amount that is from 0.5 to 0.00005 weightpercent, preferably from 0.05 to 0.0005 weight percent, and mostpreferably from 0.025 to 0.001 weight percent of the total ointmentweight. (Source: —United States Pharmacopoeia 24, United StatesPharmacopeial Convention, 1999)

Conventional therapy for osteoporosis includes; (i) estrogens, (ii)androgens, (iii) calcium supplements, (iv) vitamin D metabolites, (v)thiazide diuretics, (vi) calcitonin, (vii) bisphosphonates, (viii)SERMS, and (ix) fluorides (see, Harrison's Principles of InternalMedicine, 13^(th) edition, 1994, published by McGraw Hill Publ., ISBN0-07-032370-4, pgs. 2172-77; the disclosure of which is incorporatedherein by reference.). Any one or combination of these conventionaltherapies may be used in combination with the method of treatment usingcompounds of Formulae I as taught herein. For example, in a method oftreating osteoporosis, the vitamin D receptor modulator compounds of theinvention (e.g., as defined by formula I) may be administered separatelyor simultaneously with a conventional therapy. Alternatively, thevitamin D receptor modulator compounds of the invention may be combinedwith conventional therapeutic agents in a formulation for treatment ofosteoporosis such as set out below:

A formulation for treating osteoporosis comprising:

-   -   Ingredient (A1): a vitamin D receptor modulator represented by        formula (I), or a pharmaceutically acceptable salt or aliphatic        ester prodrug derivative thereof;    -   Ingredient (B1):        -   one or more co-agents that are conventional for treatment            osteoporosis selected from the group consisting of:            -   a. estrogens,            -   b. androgens,            -   c. calcium supplements,            -   d. vitamin D metabolites,            -   e. thiazide diuretics,            -   f. calcitonin,            -   g. bisphosphonates,            -   h. SERMS, and            -   i. fluorides.    -   Ingredient (C1): optionally, a carrier or diluent.        Typically useful formulations are those wherein the weight ratio        of (A1) to (B1) is from 10:1 to 1:1000 and preferably from 1:1        to 1:100.

Combination Therapy for Psoriasis:

Conventional therapy for psoriasis includes topical glucocorticoids,salicylic acid, crude coal tar, ultraviolet light, and methotrexate(see, Harrison's Principles of Internal Medicine, 13^(th) edition, 1994,published by McGraw Hill Publ., ISBN 0-07-032370-4, pgs. 2172-77). Anyone or combination of these conventional therapies may be used incombination with the method of treatment using compounds of Formulae Ias taught herein. For example, in a method of treating osteoporosis, thevitamin D receptor modulator compounds of the invention (e.g., asdefined by formula I) may be topically administered separately orsimultaneously with a conventional therapy. Alternatively, the vitamin Dreceptor modulator compounds of the invention may be combined withconventional therapeutic agents in a topically applied formulation fortreatment of osteoporosis such as set out below:

A formulation for treating osteoporosis comprising:

-   -   Ingredient (A2): a vitamin D receptor modulator represented by        formula (I), or a pharmaceutically acceptable salt or aliphatic        ester prodrug derivative thereof;    -   Ingredient (B2):        -   one or more co-agents that are conventional for treatment            osteoporosis selected from the group consisting of:            -   a. topical glucocorticoids,            -   b. salicylic acid, or            -   c. crude coal tar.    -   Ingredient (C2): optionally, a carrier or diluent.        Typically useful formulations are those wherein the weight ratio        of (A2) to (B2) is from 1:10 to 1:100000 and preferably from        1:100 to 1:10000.

Experimental Results:

TABLE 3 Summary of Experimental Results RXR-VDR VDR OCN Mouse Testheterodimer² EC₅₀ (nM) Promoter⁴ Hypercal⁵ Cmpd.¹ EC₅₀ (nM) (Caco-2cells)³ EC₅₀ (nM) μg/Kg/d Ex. 1 21 Ex. 3A 149/51  1261 15/18 1000 Ex. 3B396/292 2869 57/83 3000 Ex. 4A 3 Ex. 4B 15 Ex. 5 3000 42 100 Ex 6 20/1 300 0.3 10 Ex. 7 63 4 Ex. 8 1 35 4/1 100 Ex. 9 4 4 7/6 Ex. 10Da 218/25 538  8/46 Ex. 10Db 86 935 15 Ex. 11 186 1011 7 3000 Ex. 12 562/206 126120/25 4000 Ex. 12a 67 651 1 300 Ex. 12b 335/55  960 13/23 300 Ex. 1322/30 1009  89/167 3000 Ex. 14 306 3000 Ex. 15A 229/17  662 35/43 1500Ex. 15B 163 Ex. 16 35 >5000 Ex. 17 275/101 990 56/15 >3000 Ex. 18 38/4 430 1/3 1000 Ex. 19 96/12 613 12/16 2000 Ex. 20B 9/3 101 0.8/0.2 300 Ex.21 226/77  935  8/27 6000 Ex. 22 80/23 467 7/3 1000 Ex. 23 283/230 80513/40 3000 Ex. 24 3 368 0.2 Ex. 25A 8/2 340 0.4 <300 Ex. 25B 83/25 9822/3 1000 Ex. 26  6/67 651 1 300 Ex. 27 335/55  960 13/23 300 Ex. 28171/337 72 106/84  Ex. 29 93/60 958  2/11 3000 Ex. 30 101/48  698 1/31000 Ex. 31 19/33 410 1 3000 Ex. 32 89/9  345 4/1 1000 Ex. 33  1/55 4183/1 <300 Ex. 34 15/5  303 9/1 <300 Ex. 35 27 Ex. 36 242/293 698135/37  >300 Ex. 37 60 698 12 1000 Ex. 38 266/137 863 41 Ex. 39 302/204979 74/61 Ex. 40 138 694 70 Ex. 41 523 421 Ex. 42  56/316 1227 98/19 Ex.44 0.4 0.1 <300 Ex. 45 2 0.7 300 Ex. 46 6 400 2/3 3000 Ex. 47 59 81622/6  3000 Ex. 48 44 433 9/4 <1000 Ex. 49 92 859 14/40 Ex. 50 10 83 0.2300 Ex. 51 4 1.4 300 Ex. 52 81 813 4 >3000 Ex. 53 236/210 12/34 >3000Ex. 54 396 119 >3000 Ex. 55 9 920 6 AA 5.02 16 5 0.06 BB 10.32 169.818.24 20 CC 2427.7 >1000 DD 109.44 31.1 1000 EE 429.99 891.16 341.25 1000FF 3 57

TABLE 4 Summary of Experimental Results Test Kera. Prolif. IL-10. Cmpd.¹IC₅₀ (nM) IC₅₀ (nM) Ex. 1 Ex. 3A Ex. 3B Ex. 4A Ex. 4B Ex. 5 375 Ex 6 255 Ex. 7 18 Ex. 8 330 Ex. 9 985 Ex. 10Da 1000 Ex. 10Db 1000 Ex. 11 308478 Ex. 12 Ex. 12a 4 52 Ex. 12b Ex. 13 Ex. 14 Ex. 15A 117 Ex. 15B Ex. 16Ex. 17 1000 Ex. 18 1000 47 Ex. 19 82 142 Ex. 20B 3 4 Ex. 21 223 1050 Ex.22 4 39 Ex. 23 40 27 Ex. 24 Ex. 25A 1105 40 Ex. 25B 26 158 Ex. 26 4 52Ex. 27 Ex. 28 240 Ex. 29 49 153 Ex. 30 20 123 Ex. 31 21 295 Ex. 32 1000106 Ex. 33 6 19 Ex. 34 25 45 Ex. 35 40 Ex. 36 139 Ex. 37 55 229 Ex. 38Ex. 39 508 Ex. 40 1000 Ex. 41 Ex. 42 50 Ex. 44 28 6 Ex. 45 32 15 Ex. 4621 33 Ex. 47 1000 Ex. 48 1000 Ex. 49 1000 Ex. 50 3 4 Ex. 51 26 19 Ex. 5252 154 Ex. 53 224 Ex. 54 Ex. 55 AA 120 1.2 BB 10 28 CC DD 1060 EE FF 1030.5

Explanation of Table 5 and 6 Column Numerical Superscripts:

1. Test Compound numbers refer to the products of the correspondingExample Nos. that is, compounds within the scope of the invention. Forexample, the number “Ex. 2” refers to the compound,3′-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3′-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane,prepared in Example 2. The control experiments are done with the doubleletter coded compounds identified as follows:

“AA”=1α,25-dihydroxyvitamin D₃

“BB”=3-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1,2-diol

“CC”=1-(4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-cyclohexyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one

“DD”=compound represented by the formula:

“EE”=compound represented by the formula:

“FF”=calcipotriol (structural formula below):

2. The RXR-VDR heterodimerization (SaOS-2 cells) test is described inthe “Assay” section of the Description, infra.

3. The VDR CTF (Caco-2 cells) test is described in the “Assay” sectionof the Description, infra.

4. The OCN Promoter test is described in the “Assay” section of theDescription, infra.

5. The Mouse Hypercalcemia test is described in the “Assay” section ofthe Description, infra.

6. The keratinocyte proliferation assay is described in the “Assay”section of the Description, infra.

7. The IL-10 induction assay is described in the “Assay” section of theDescription, infra.

Assay Methods Use of the Assay Methods:

The evaluation of the novel compounds of the invention for osteoporosisand other related diseases is done using a plurality of test results.The use of multiple assays is necessary since the combined properties of(i) high activity for the vitamin D receptor, and (ii) prevention ofhypercalcemia must be achieved to have utility for the methods oftreating diseases, which are also, aspects of this invention. Some ofthe tests described below are believed related to other tests andmeasure related properties of compounds. Consequently, a compound may beconsidered to have utility in the practice of the invention if is meetsmost, if not all, of the acceptance criteria for the above describedtests.

The evaluation of the novel compounds of the invention for psoriasis isdone using the Keratinocyte Proliferation Assay in combination withother assays that measure inhibition of IL-2 production and stimulationof IL-10 production in peripheral blood mononuclear cells (PBMCs).

Brief Description, Utility and Acceptance Criteria for the AssayMethods: 1. The RXR-VDR Heterodimer Assay:

This assay provides the VDR activity of a test compound. It is desirableto have low EC50 values for a compound in this assay. The lower the EC50value, the more active the compound will be as a VDR agonist. Desiredassay results are EC50 values less than or equal to 600 nM. Preferredassay results are less than 250 nM, and most preferably less than 150nM.

2. The Caco-2 cell Co-transfection Assay:

The Caco-2 cell assay is an indicator for the undesirable condition ofhypercalcemia. This co-transfection assay is a surrogate assay for invivo calcemic activity of VDR ligands. It is desirable to have high EC50values for a test compound in this assay. The higher the EC50 values fora compound the less calcemic it will be in vivo. Desired assay resultsare EC50 greater than or equal to 300 nM. Preferred assay results aregreater than 1000 nM.

3. The OCN (osteocalcin) Promoter Assay

The OCN Promoter Assay is an indicator and marker for osteoporosis.Desired assay results are EC50 less than or equal to 325 nM. Preferredassay results are less than 50 nM.

4. The Mouse Hypercalcemia Assay

The Mouse Hypercalcemia Assay is a six day hypercalcemia test fortoxicity and selectivity. Acceptable test results are levels greaterthan 300 μg/kg/day. Preferred assay results are levels greater than 1000μg/kg/day.

5. The Keratinocyte Proliferation Assay

This Assay is indicative for the treatment of psoriasis. An acceptabletest result is IC50 value of less than or equal to 300 nM. Preferredassay results are IC50 values of less than 100 nM.

6. The IL-10 induction Assay

This is an in vitro efficacy assay for psoriasis, abscess and adhesion.Psoriasis involves both keratinocytes and immune cells. IL-10 is aunique cytokine because it is anti-inflammatory and immunosuppressive.This assay tells us whether a VDRM is able to function as an agonist inPBMCs (primary blood mononuclear cells) or not. A lower EC50 value isdesirable in this assay since a compound with a lower EC50 value will bea better agonist in PBMCs. An acceptable test result is an EC50 value ofless than 200 nM. Preferred assay results are EC50 values of less than100 nM.

7. Other Compound Assay Standards

An alternative measure of the therapeutic index (bone efficacy vx.hypercalcemia) of compounds of the invention for treatment ofosteoporosis is a numerical ratio calculated as follows:

Dose Threshold Needed to Induce Hypercalcemia Divided by Dose ThresholdNeeded for Bone Efficacy

An alternative measure of the therapeutic index (in vivo keratinocyteproliferation vs. hypercalcemia) of compounds of the invention fortreatment of psoriasis is a numerical ratio calculated as follows:

Dose Threshold Needed to Induce Hypercalcemia Divided by Dose ThresholdNeeded to Induce Keratinocyte Proliferation

For the above ratios, Dose Thresholds are determined from dose responsecurve data.

Details of the Assay Methods: (1) Materials and Method for RXR-VDRHeterodimerization Assay: Transfection Method:

FuGENE 6 Transfection Reagent (Roche Cat # 1 814 443)

Growth Media:

D-MEM High Glucose (Gibco BRL Cat # 11054-020), 10% FBS, 1%antibiotic-antimycotic (Ab-Am)

FBS heat inactivated (Gibco BRL Cat # 10092-147)

Ab-Am (Gibco BRL Cat # 15240-062) Cells:

Grow SaOs-2 cells in T-152 cm² culture flasks in growth media.

Keep the density at 5−6×10⁵ cells/ml

Passage cells 1:3 twice a week

Add Trypsin EDTA (Gibco BRL Cat # 25300-020) and incubate

Resuspend cells in plating media and transfer into growth media.

Wash Media:

HBSS Low Glucose Without Phenol Red (Gibco BRL Cat # 14175-095), 1%Ab-Am Plating Media:

D-MEM Low Glucose Without Phenol Red (Gibco BRL Cat # 11054-020), 1%Ab-Am D-MEM

Stripped FBS (Hyclone Cat# SH30068.03 Lot # AHM9371) Ab-AmTransfection/Treatment Media:

D-MEM Low Glucose Without Phenol Red only

T-152 cm² culture flask:

Use Coming Coastar T-152 cm² culture flask (Cat # 430825) to grow thecells Flat well Plates:

Use well plate to plate cells

Use Deep well plate sterile to make up treatment media.

Luciferase Assay Reagent:

Use Steady-Glo Luciferase Reagent from Promega (Cat # E2550) Consistsof:

a. E2533 Assay Substrate, lypholized product andb. E2543 Assay Buffer.

Thaw at room temperature

Store

Day 1: Cell Plating Cell Harvesting

Aspirate media from culture flask, rinse cells with HBSS and aspirate.Add trypsin and incubate.When cells appear detached, resuspend cells in growth media.Transfer into a new flask with fresh growth media for passaging thecells.Plate well plates and two extra plates

D. Cell Count

Mix the cell suspension using pipetteUse Hematocytometer to count the cellsLoad cell suspension onto the hemocytometer chamber Count cells.

Plate Seeding:

Use plating media 10% Stripped FBS in D-MEM Low Glucose, Without PhenolRed, 1% Ab-AmPlate 14 plates @ 165 μl/well.In sterile flask add cell suspension to plating media.

Mix.

Add cells/well.Place the cells in the incubator.Cells should be about 75% confluent prior to transfection.

Step 1: DNA and Media

Add plain DMEM media to tubes for mixing the DNAAdd the Reporter gene pFR-LUC

Add the Gal-4—RXR-DEF and VP16-VDR-LBD Step 2: FuGENE and Media

Prepare plain DMEM media in a ubes for mixing FuGENE

Add FuGENE 6 Transfection Reagent Incubate Step 3: FuGENE, DNA and MediaComplex

Add FuGENE Media complex from step 2 to DNA Media complex from step 1IncubateStep 4: FuGENE, DNA and Media Complex to-well plateAdd FuGENE-DNA-Media complex from step 3 to each plate Incubate.

Day 3: Dosing Treatment preparation

Allow for transfection timeMake a stock solution of the compounds in DMSOVortex until all the compounds has been dissolved.Further dilute in D-MEM (Low Glucose—With out Phenol Red)Add compounds in quadruplicate to give final volume Incubate.

Day 4: Luciferase Assay

Read the plates after drug treatmentRemove part of media from all the wells and leave remainderAdd Steady-Glo Luciferase Reagent mixture/wells Incubate

-   Count each well using a Luminescence counter, Top Count NXT by    Packard Set a delay between plates to reduce the background.

(2) Materials and Method for The Caco-2 Cell Assay:

-   -   Caco-2 cells, grown in phenol red free, DMEM (Invitrogen,        Carlsbad, Calif.) containing 10% charcoal-stripped FCS (Hyclone,        Logan, Utah), were transfected with Fugene 6 reagent (Roche        Diagnostics, Indianapolis, Ind.). Cells (5000/well) were plated        18 h before transfection in a 96 well plate. The Cells were        transfected with Gal-4-responsive reporter pFRLuc (150 ng,        Stratagene, La Jolla Calif.) and the receptor expression vector        pGal4-VDR-LBD (10 ng), along with Fugene 6 reagent (0.2        μl/well). The DNA-Fugene complex was formed by incubating the        mixture for 30 min at room temperature. The cells were        transfected in triplicate for 5 h, and treated with various        concentrations of VDR ligands (form 0.01 nM to 10,000 nM        concentration range) 18 h post-transfection. The luciferase        activity was quantified using Steady-Glo reagent kit (Promega,        Madison, Wis.) as per manufacturer's specifications.

(3) Materials and Method for The OCN Promoter Assay:

-   -   The activation of osteocalcin by VDR ligands was evaluated in a        rat osteoblast-like cell line RG-15 (ROS 17/2.8) stably        expressing rat osteocalcin promoter fused with luciferase        reporter gene. The stable cell lines were established as        reported before (Activation of Osteocalcin Transcription        involves interaction of protein kinase A- and Protein kinase        C-dependent pathways. Boguslawski, G., Hale, L. V., Yu, X.-P.,        Miles, R. R., Onyia, J. E., Santerre R. F., Chandrasekhar, S. J.        Biol. Chem. 275, 999-1006, 2000). Confluent RG-15 cells        maintained in DMEM/F-12 medium (3:1) containing 5% FBS, 300        □g/ml G418 and at 37° C. under 5% CO₂/95% air atmosphere were        trypsinized (0.25% trypsin) and plated into white opaque 96-well        cell culture plates (25000 cells/well). After 24 hr, cells (in        DMEM/F-12 medium+2% FBS) were treated with various        concentrations of compounds, dissolved in DMSO. The final DMSO        concentration remained at 0.01% (v/v). After 48 hr treatment,        the medium was removed, cells were lysed with 50 □l of lysis        buffer (From Luciferase reporter assay system, Roche        Diagnostics, Indianapolis, Ind.) and assayed for luciferase        activity using the Luciferase Reporter Gene Assay kit from        Boehringer Mannheim as per manufacturer's specifications.

(4) Materials and Method for The Mouse Hypercalcemia Assay:

Weanling, virus -antibody-free, five to six weeks old female DBF mice(Harlan, Indianapolis, Ind.) are used for all the studies. Animals areallowed to acclimate to local vivarium conditions for 2 days. Mice aremaintained on a 12 hr light/dark cycle at 22° C. with ad lib access tofood (TD 5001 with 1.2% Ca and 0.9% P, Teklad, Madison, Wis.) and water.The animals then are divided into groups with 4-5 mice per group.Different doses of test compounds prepared in 10% Ethanol and 90% sesameoil are administered to mice orally via gavage for 6 days. 1α-25(OH)₂D₃0.5 μg/kg/d was also given to one group of mice as the positive control.Serum ionized calcium is evaluated at 6 hours after the last dosingunder isoflurane anesthesia by Ciba-Coming Ca++/PH Analyzer, (Model 634,Chiron Diagnostics Corp., East Walpole, Mass.). Raw data of groupdifferences is assessed by analysis of variance (ANOVA) using Fisher'sprotected least significant difference (PLSD) where the significancelevel was P<0.05.

(5) The Keratinocyte Proliferation Assay:

KERtr cells (Human skin keratinocyte transformed with a retrovirusvector, obtained from ATCC) were plated in 96-well flat-bottomed plates(3000 cells/well) in 100 □l keratinocyte serum free medium supplementedwith bovine pituitary extract in the absence of EGF (Life Technologies,Rockville, Md.) and incubated at 37° C. for two days. The cells weretreated with various concentrations of VDR ligands (ten-fold serialdilution from 10,000 nM to 0.1 nM in triplicate), dissolved in 100 □lkeratinocyte serum free medium supplemented with bovine pituitaryextract in the absence of EGF and incubated at 37° C. for 72 hr. BrdU(5-bromo-2′-deoxyuridine) incorporation was analyzed as a measure of DNAreplication (Cell proliferation ELISA kit, Roche Diagnostics,Indianapolis, Ind.) and absorbance was measured at 405 nm. Potencyvalues (IC₅₀) values were determined as the concentration (nM) ofcompound that elicited a half-maximal response.

(6) Materials and Method for human IL-10 Induction Assay:Isolation of peripheral blood mononuclear cells (PBMCs):

-   -   A. Collect 50 ml of human blood and dilute with media,        RPMI-1640.    -   B. Prepare sterile tubes with ficol.    -   C. Add diluted blood to tubes.    -   D. Centrifuge.    -   E. Discard the top layer and collect the cells from middle        layer.    -   F. Divide all cells into four tubes and add media.    -   G. Centrifuge.    -   H. Aspirate off media and resuspend.    -   I. Collect all cells    -   J. Centrifuge. at 1200 rpm for 10 minutes.    -   K. Resuspend in RPMI-1640 with 2% FBS and count cells        Stimulation of PBMC:    -   L. Prepare TPA in DMSO.    -   M. Dissolve PHA in water.    -   N. Plate TPA/PHA treated PBMCs in well plates.    -   O. Incubate.    -   Treatment:    -   P. Prepare all compound dilutions in plain RPMI-1640 media.    -   Q. Add diluted compound.    -   R. Incubate.    -   Sample Collection and assay:    -   S. Remove all the cells by centrifugation and assay the        supernatant for IL-10 by immunoassay.

-   1) T. Perform IL-10 assay using anti-human IL-10 antibody coated    beads, as described by the manufacturer (Linco Research Inc., St.    Charles, Mo.).

1-29. (canceled)
 30. A compound represented by formula I or apharmaceutically acceptable salt thereof:

wherein; R and R′ are independently methyl or ethyl; R₁ and R₂ areindependently selected from hydrogen, halo, or C₁-C₅ alkyl; Z_(B) is agroup represented by the formula:

wherein (L₁)- is a bond or —(CH₂)_(m)—O—; (L₂)- is a bond or—(CH₂)_(m)—C(R40)(R40)—; (L₃)- is selected from the group consisting of

wherein m is 0, 1, or 2, and each R40 is independently hydrogen or C₁-C₅alkyl; R_(B) is a branched C₃-C₅ alkyl; Z_(C) is selected from: —C(O)OH,—C(O)O(C₁-C₂ alkyl), —C(O)N(H)—CH₂—C(O)OH, —C(O)N(H)—CH₂—C(O)OC₁-C₄alkyl, —C(O)N(Me)-CH₂—C(O)OH, —C(O)N(Me)-CH₂—C(O)OC₁-C₄ alkyl,—C(O)N(H)—CH(Me)-C(O)OH, —C(O)N(H)—CH(Me)-C(O)OC₁-C₄ alkyl,—C(O)N(H)—CH(Et)-C(O)OH, —C(O)N(Me)-CH(Me)—C(O)OH,—C(O)N(H)—C(Me)₂-C(O)OH, —C(O)N(H)—C(Me)₂-C(O)OC₁-C₄ alkyl,—C(O)N(Me)-C(Me)₂-C(O)OH, C(O)NHSO₂(C₁-C₄ alkyl), —C(O)N(H)CH₂CH₂SO₂Me,—CH₂N(H)CH₂CH₂SO₂CH₃, —CH₂CH₂CO₂H, —CH₂CH₂C(O)OC₁-C₂ alkyl—CH₂CH₂C(O)NH₂, —CH₂CH₂C(O)NHMe, —CH₂CH₂C(O)NMe₂, —CH═CHC(O)NMe₂,—CH₂—O—CH₂C(O)OH, —CH₂—O—CH₂C(O)OC₁-C₄ alkyl, -5-tetrazolyl,

provided that the compound is not


31. A compound of claim 30 or a pharmaceutically acceptable saltselected from C-1 to C-30:


32. The compound of claim 30 or a pharmaceutically acceptable salt ofthe compound represented by the formula:


33. The compound of claim 30 or a pharmaceutically acceptable salt ofthe compound represented by the formula:


34. A compound of claim 30 wherein sodium or potassium is a cation forthe pharmaceutically acceptable salt.
 35. A pharmaceutical compositioncomprising a compound of claim 30, or a pharmaceutically acceptablesalt, together with a pharmaceutically acceptable carrier or diluent.36. A composition for treating osteoporosis comprising: a compoundaccording to claim 30, or a pharmaceutically acceptable salt; one ormore co-agents selected from: estrogens; androgens; calcium supplements;thiazide diuretics; calcitonin; bisphosphonates; SERMs, and fluorides;and optionally, a carrier or diluent.
 37. A method of treatingosteoporosis or psoriasis in an animal in need thereof, wherein themethod comprises administering a pharmaceutically effective amount of acompound according to claim 30, or a pharmaceutically acceptable salt.38. The method of claim 37 for the treatment of psoriasis.
 39. Themethod of claim 37 for the treatment of osteoporosis.